Basic Principles of Basic Principles of

PharmacologyPharmacology Prof. Suheil ZmeiliProf. Suheil ZmeiliFaculty of MedicineFaculty of Medicine

Department of PharmacologyDepartment of PharmacologyUniversity of JordanUniversity of Jordan

E-mail: szmeili@ju.edu.joE-mail: szmeili@ju.edu.jo

Objectives:Objectives:- To know definition of a drug- To know definition of a drug- To know branches of pharmacology- To know branches of pharmacology- Describe stages or phases of drug - Describe stages or phases of drug

trials (preclinical and clinical)trials (preclinical and clinical)- Understand ethics of the use of - Understand ethics of the use of

drugs in humansdrugs in humans

** Pharmacology** Pharmacology Pharmakon = Drug; Logos = SciencePharmakon = Drug; Logos = ScienceThe study of drugs and their interactions The study of drugs and their interactions

with living systemswith living systemsWide term which includes:Wide term which includes:- The investigation of the biochemical and - The investigation of the biochemical and

physiological effects of drugsphysiological effects of drugs- The study of drug absorption; distribution; - The study of drug absorption; distribution;

metabolism and excretionmetabolism and excretion- The knowledge about the history; sources; - The knowledge about the history; sources;

physical and chemical properties and physical and chemical properties and therapeutic uses of drugstherapeutic uses of drugs

History The story of pharmacology is rich in

exiting and filled with accidental discoveries

The oldest forms of healthcare is the herbal medicine

Modern pharmacology is thought to have begun in the early 1800s, at which the chemists were making a remarkable progress in isolating active ingredients from a complex mixture such as morphine and cocaine

In the 20th century, the grow in the field of pharmacology became exponential:

a. no longer needed to rely on the natural sources, hundred of new drugs could be synthesized and tested in relatively short time

b. it became possible to understand how drugs produce their effect

The optimum goal

Pharmacology is a keystone for a prescribing doctor, as they can impact proper dosage, what time a drug should be taken, how a drug should be delivered and for how long?

** Drug** Drug- A chemical substance that is - A chemical substance that is

primarily used to reverse a primarily used to reverse a pathophysiological defect = diseasepathophysiological defect = disease

= Virtually all chemicals may be = Virtually all chemicals may be drugsdrugs

= All drugs are toxins but not all = All drugs are toxins but not all toxins are drugstoxins are drugs

FDA approved definition of a drugFDA approved definition of a drugA chemical substance that is mainly A chemical substance that is mainly

used to:used to: - treat, - treat, - control, - control, - prevent, - prevent, - diagnose a specific disease - diagnose a specific disease - or to prevent pregnancy!!!- or to prevent pregnancy!!!

* * Clinical PharmacologyClinical PharmacologyThe study of drugs in humans (the The study of drugs in humans (the

interaction of drugs and people)interaction of drugs and people)It involves study of drugs in patients It involves study of drugs in patients

as well as in healthy volunteers as well as in healthy volunteers during new drug developmentduring new drug development

It deals with patients or diseases or It deals with patients or diseases or pathophysiological processes and pathophysiological processes and how drugs reverse them how drugs reverse them

HumanMan;Woman

Pathophysiological Process=Disease

ManagementDrugs

Hypothesis=Idea

Assessment of efficacyIn vitro & in vivo studies

Assessment of safety

PharmaceuticalProcess

KineticsDynamics

Administration

Drug discovery and Drug discovery and pharmaceutical processpharmaceutical process

Drug discovery & developmentDrug discovery & development

MAJOR OBJECTIVEMAJOR OBJECTIVE

TO HAVE DRUG AT SITE OF ACTION TO HAVE DRUG AT SITE OF ACTION IN PROPER CONCENTRATION IN PROPER CONCENTRATION GOOD ENOUGH TO REVERSE GOOD ENOUGH TO REVERSE

DEFECT WITHOUT PRODUCING DEFECT WITHOUT PRODUCING SIDE OR TOXIC EFFECTS SIDE OR TOXIC EFFECTS

• Pharmaceutical processPharmaceutical process; drug in dosage form:; drug in dosage form:Is the drug getting into patient?Is the drug getting into patient?• Pharmacokinetic process:Pharmacokinetic process:Is the drug getting to its site of action?Is the drug getting to its site of action?• Pharmacodynamic process:Pharmacodynamic process:Is the drug producing the required pharmacological Is the drug producing the required pharmacological

effect?effect?• Therapeutic processTherapeutic process (clinical pharmacology): (clinical pharmacology):Is the pharmacological effect being translated into Is the pharmacological effect being translated into

therapeutic effect?therapeutic effect?• PhrmacogeneticsPhrmacogeneticsIndividual variations in responding to drugs + gene Individual variations in responding to drugs + gene

therapytherapy

Drug discovery & developmentDrug discovery & development1. Starts with prediction=an idea & 1. Starts with prediction=an idea &

hypothesishypothesisWhat helps?What helps? - Awareness of the beneficial effects of - Awareness of the beneficial effects of

plants and animal products (natural plants and animal products (natural sources)sources)

- Chemical identification of a wide variety - Chemical identification of a wide variety of natural mediators and the possibility of natural mediators and the possibility of modifying them chemically of modifying them chemically

e.g. epinephrine, norepinephrinee.g. epinephrine, norepinephrine acetylcholineacetylcholine histaminehistamine prostaglandinsprostaglandins endogenous opioidsendogenous opioids hormoneshormones……etcetc - Avoiding chemicals with highly - Avoiding chemicals with highly

reactive groups (toxic) reactive groups (toxic)

22 . .Design and synthesis of useful drugs Design and synthesis of useful drugs or substances through simple or substances through simple techniques or with the help of techniques or with the help of advanced technologyadvanced technologye.g. a plant → fractionation, e.g. a plant → fractionation, chromatographic experiments → chromatographic experiments → identification of the active identification of the active ingredients → isolation → purification ingredients → isolation → purification → good drug (recently most drugs of → good drug (recently most drugs of plant source could be synthesized)plant source could be synthesized)

An animal → isolation of a substance An animal → isolation of a substance (insulin)(insulin)

Simple peptides → a.a sequencing Simple peptides → a.a sequencing machinemachine

Complex proteins → recombinant DNA Complex proteins → recombinant DNA technology=genetic engineeringtechnology=genetic engineering

** Receptology studies** Receptology studiesAllowed synthesis of huge number of Allowed synthesis of huge number of

agonists and antagonistsagonists and antagonists

3. Preclinical studies3. Preclinical studiesStudies on tissues and whole Studies on tissues and whole

animalsanimals- Determine efficacy- Determine efficacyIsolated tissue e.g. bronchi → organ Isolated tissue e.g. bronchi → organ

path → testing drugpath → testing drug……etcetcAnimal models Animal models → → drug ↓ BPdrug ↓ BP→ → drug ↓ blood sugar leveldrug ↓ blood sugar level

- Determine pharmacokinetic parameters- Determine pharmacokinetic parametersAbsorption, distribution, metabolismAbsorption, distribution, metabolism……etcetc- Determine pharmacodynamics (MOA)- Determine pharmacodynamics (MOA)- Assessment of drug toxicity=safety- Assessment of drug toxicity=safety. Acute toxicity studies. Acute toxicity studiesDetermination of LD50; Margin of safetyDetermination of LD50; Margin of safety……

etcetc. Subacute and chronic toxicity studies. Subacute and chronic toxicity studiesRepeated dose studiesRepeated dose studies

Daily observation of animals Daily observation of animals (wt., food and water intake ..)(wt., food and water intake ..)

Obtaining biological samples Obtaining biological samples (blood; urine)(blood; urine)

Obtaining tissues (liver; Obtaining tissues (liver; spleen; stomachspleen; stomach……etc) for etc) for histopathological exam or histopathological exam or studiesstudies

- Special toxicology studies- Special toxicology studies. Mutagenicity (genotoxicity) tests. Mutagenicity (genotoxicity) testsCould delineate the induction of Could delineate the induction of

gene mutations (bacterial gene mutations (bacterial mutagenicity test or administration mutagenicity test or administration of drug to pregnant animalsof drug to pregnant animals……etc)etc)

Some mutations could result in the Some mutations could result in the development of cancerdevelopment of cancer

. Carcinogenicity studies. Carcinogenicity studiesNot always required prior to early Not always required prior to early

studies in man unless there is a high studies in man unless there is a high suspicion that the drug could be suspicion that the drug could be carcinogenic e.g. suspicion of carcinogenic e.g. suspicion of mutagenicity; highly reactive groups on mutagenicity; highly reactive groups on drug; histopathological abnormalitiesdrug; histopathological abnormalities……

Required if the use of drug in man for Required if the use of drug in man for more than one year or +ve mutagenic more than one year or +ve mutagenic test test

Clinical drug trials ( mainly 4 phases)Clinical drug trials ( mainly 4 phases)- Phase 0- Phase 0Phase 0 or first-in-human trials is a Phase 0 or first-in-human trials is a

recent phase approved in accordance recent phase approved in accordance with the United States FDAwith the United States FDA’’s 2006 s 2006 Guidelines Guidelines

Phase 0 trials are also known as human Phase 0 trials are also known as human microdosing microdosing studies and are designed to studies and are designed to speed up the development of promising speed up the development of promising drugs by establishing very early on drugs by establishing very early on whether the drug or agent behaves in whether the drug or agent behaves in human subjects as was expected from human subjects as was expected from preclinical studiespreclinical studies

Distinctive features of Phase 0 trials Distinctive features of Phase 0 trials include the administration of single include the administration of single subtherapeutic dosessubtherapeutic doses of the study of the study drug to a small number of subjects drug to a small number of subjects (10 to 15) to gather preliminary data (10 to 15) to gather preliminary data on the drug's pharmacokinetics and on the drug's pharmacokinetics and pharmacodynamics pharmacodynamics

A Phase 0 study gives no data on safety A Phase 0 study gives no data on safety or efficacy, being by definition a dose or efficacy, being by definition a dose too low to cause any therapeutic too low to cause any therapeutic effect. effect.

Phase 0 studies enable go/no-go Phase 0 studies enable go/no-go decisions to be based on relevant decisions to be based on relevant human models instead of relying on human models instead of relying on sometimes inconsistent animal datasometimes inconsistent animal data

Questions have been raised by experts Questions have been raised by experts about whether Phase 0 trials are about whether Phase 0 trials are useful, ethically acceptable, feasible, useful, ethically acceptable, feasible, speed up the drug development speed up the drug development process or save money, and whether process or save money, and whether there is room for improvementthere is room for improvement

- Phase I- Phase IInvolves the use of a drug in Involves the use of a drug in

humans for the first timehumans for the first timeIt establishes dose level at which It establishes dose level at which

signs of toxicity first appearsigns of toxicity first appearConducted on 20-80 Conducted on 20-80 healthyhealthy men men

with ages 18-45 yrswith ages 18-45 yrs

Usually a single dose is used initially and Usually a single dose is used initially and if no side effects exhibited, the dose is if no side effects exhibited, the dose is increased progressively until sufficient increased progressively until sufficient serum level is achieved (therapeutic serum level is achieved (therapeutic level) or some toxic effects appearlevel) or some toxic effects appear

Such studies are conducted in hospitalSuch studies are conducted in hospitalIf no side effects result from single dose, If no side effects result from single dose,

multiple dose studies should be initiatedmultiple dose studies should be initiated=bioavailability-bioequivalence studies=bioavailability-bioequivalence studies

- Phase II- Phase IIIf phase I studies prove that the drug If phase I studies prove that the drug

is safe to continue, the new drug is is safe to continue, the new drug is administered to administered to patientspatients for the first for the first timetime

All patients should have only one All patients should have only one problem (one disease)problem (one disease)

It assesses efficacy and establishes It assesses efficacy and establishes optimal dose range in patients (dose-optimal dose range in patients (dose-response studies are important)response studies are important)

Phase II studies are conducted on 80-100 Phase II studies are conducted on 80-100 patients (certain countries ask for 50-patients (certain countries ask for 50-300 patients)300 patients)

Also patients are observed for toxicity to Also patients are observed for toxicity to assess safety of the drugassess safety of the drug

- Phase III- Phase IIISimilar to phase II but conducted on larger Similar to phase II but conducted on larger

number of patients (several hundreds to number of patients (several hundreds to thousands; 250-1000 reasonable)thousands; 250-1000 reasonable)

It also assesses safety and efficacyIt also assesses safety and efficacyCould detect effects/side effects not Could detect effects/side effects not

observed in phase IIobserved in phase II

- Phase IV- Phase IVPost-marketing studiesPost-marketing studiesControlled and uncontrolled studies are Controlled and uncontrolled studies are

often conducted after drug approval and often conducted after drug approval and marketingmarketing

Double-blind; single-blind placebo Double-blind; single-blind placebo controlled studies are usually conductedcontrolled studies are usually conducted

It further assesses safety & efficacy of It further assesses safety & efficacy of drugsdrugs

Phase IV clinical drug trial studies allow Phase IV clinical drug trial studies allow for comparisons between different for comparisons between different drugs used for the same diseasedrugs used for the same disease

In addition, phase IV studies provide In addition, phase IV studies provide evidence of a new use to the drug e.g. evidence of a new use to the drug e.g.

Aspirin-antiplateletAspirin-antiplatelet Sildenafil citrate-ED...Sildenafil citrate-ED...

AFTER ALL THESE CLINICAL DRUG AFTER ALL THESE CLINICAL DRUG TRIALS THE DRUG IS USUALLYTRIALS THE DRUG IS USUALLY APPROVED BY NATIONAL ORAPPROVED BY NATIONAL OR INTERNATIONAL REGULATORY INTERNATIONAL REGULATORY AUTHORITIES AND IS LICENSED AUTHORITIES AND IS LICENSED

FORFOR GENERAL PRESCRIBING GENERAL PRESCRIBING

Ethics of the use of drugs in humansEthics of the use of drugs in humans• Full detailed protocol has to be Full detailed protocol has to be

approved by the ethical committee, approved by the ethical committee, the institutional review board (IRB)the institutional review board (IRB)

• All subjects should sign an informed All subjects should sign an informed consent formconsent form

• All subjects should be insured for All subjects should be insured for life and damage life and damage

** Branches of pharmacology usually ** Branches of pharmacology usually answer all of the following questions:answer all of the following questions:

- How much of a drug to give? Dose- How much of a drug to give? Dose- How frequent a drug should be given? - How frequent a drug should be given?

Related to the biological half-life (tRelated to the biological half-life (t1/21/2))- When to give it? Before or after meals; - When to give it? Before or after meals;

at bed time, PRN...at bed time, PRN...- How to give it? administration ... etc - How to give it? administration ... etc

Terms Medication=Drug: is a substance

administered for diagnosis, cure=treatment, control or prevention

Prescription: the written direction for the preparation and the administration of the drug

The therapeutic effect: is the primary effect intended that is the reason the drug is prescribed such as morphine sulfate is analgesia.

Side effect: secondary effect of the drug is one that is unintended. side effects are usually predictable and may be harmless in most cases

Drug toxicity: deleterious effect of the drug on an organism or tissue, resulting from overdose or external use

Drug interaction: occur when administration of one drug before or after alter the effect of one or both drug

Drug misuse: is the improper use of common medications in way that lead to acute and chronic toxicity for example laxatives, antacids and vitamins

Drug abuse: is an inappropriate intake of substance either continually or periodically

Drug dependence: is a person’s reliance on or need to take drug or substance. There are two types of dependence:

a. Physiological dependence: is due to biochemical changes in body tissues which become requiring the substance for normal function

Psychological dependence: is emotional reliance on a drug to maintain a sense of wellbeing

Drug habituation: denotes a mild form of psychological dependence

Illicit drugs: also known as street drugs; are those sold illegally

OTC Dugs: over the counter drugs are those which are sold without prescription