INTRODUCTION TO PHARMACOLOGY MUSTAFEEZ BABAR

COURSE CONTENT General Principles of Pharmacology Basic Pharmacology Clinical Pharmacology-(Selected Organ systems) Molecular Basis of Pharmacology Pharmacological Parameters and Calculations for drug candidate selection

ASSESSMENT CRITERIA Sessionals = (15+5)*2 Assignment/ presentation = 10 Terminal = 50

the main focus of the course would be to help you people get the basic skills for converting a chemical into a drug i.e., by training you to identify drug targets, potential groups of drugs that can be used, the pharmacological and pharmaceutical parameters and the development of appropriate dosage form.

PRINCIPLES OF PHARMACOLOGY “Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous” (William Withering, “discoverer” of digitalis, 1789) Paul Insel, M.D. (UCSD) in Molecular Basis of Drug Action and Disease Therapy

Lecture Outline This lecture will answer the following questions: What is pharmacology? Why are drugs important for human health and scientific research? How do drug efficacy and toxicity contribute to therapeutic success, therapeutic failures and medical errors? What is the “therapeutic partnership”? What are some major principles of pharmacotherapy? Where does one obtain reliable information about drugs? Can drug therapy be individualized/personalized? What new efforts in pharmacotherapy and pharmacology are on the horizon? How are drugs developed and approved? 2

What is pharmacology? Pharmacology (from pharmakon, the Greek word for drug) is the study of drugs (substances that produce changes in the body) and the characterization of their: Structure, targets, and mechanisms of action Distribution in and handling by the body Effects on the body, including desirable responses (efficacy) and undesirable side-effects (toxicity) Drugs include caffeine, nicotine, alcohol in addition to chemicals that are abused (e.g., cannabis, heroin, etc.), food constituents (vitamins, minerals, amino acids, etc.) and cosmetics. Pharmacology can be studied at multiple “levels”: molecular, (sub)cellular, tissue, whole animal, or population Clinical pharmacology is the study of drugs in human patients Toxicology is the study of harmful rather than therapeutic effects Pharmacy involves manufacture, preparation, and dispensing of drugs 3

What is pharmacology? Pharmacokinetics (“what the body does to a drug”) and phamacodynamics (“what a drug does to the body”) are the two key aspects of pharmacology In research, many experimentalists in the biological sciences use drugs to produce or block responses and as a means to infer mechanisms (of cell, tissue/organ, organismal responses). In addition, others seek new ways to treat disease Prescribing drugs is what MD’s “do” and drugs are the raison d’etre of pharmacists. Understanding the principles of pharmacology is thus “central” to the efforts of MD’s, PharmD’s and most biomedical researchers 4

Why are drugs important for health and scientific research? From early in human history, pharmacologically active substances (e.g., from plants, animals) have been used to ward off or treat disease Drugs can be molecules synthesized in the body (e.g., hormones or neurotransmitters [e.g. dopamine, epinephrine, acetylcholine]) or molecules not synthesized in the body (i.e., xenobiotics, from the Greek xenos, meaning “stranger”) Poisons are drugs that almost exclusively have harmful effects Discovery and development of drugs (including immunotherapy/ vaccinations) has been a major factor that has increased life span and improved the quality of life New scientific insights—in some cases, inferred from novel mechanisms of action– have been essential to this progress, together with controlled clinical trials, in particular, randomized, double-blind trials In parallel (especially in recent years) has been the promotion of “alternative” and “complementary” treatments, many (most) of which have not undergone rigorous scientific validation 5

Why are drugs important for health and scientific research? The search for “magic bullets”—agents that treat disease or produce desirable effects but lack harm— and ways to improve such agents has driven scientific discovery for >100 years There are very few magic bullets* with high benefits and very low risk The challenge is to identify, test, approve and ultimately use drugs that maximize efficacy but minimize toxicity Primum non nocere: “First do no harm” Because of problems (including deaths) that have occurred, governments use approval processes (which tend to emphasize safety>efficacy) before drugs can be marketed and prescribed. *Examples: selective toxicity of antimicrobials that target bacterial cell walls (lacking in animals/humans) or enzymes found only in micro-organisms 6

Important Terminology Pharmacodynamics (“drug action”) includes the measurement of responses to drugs and how such responses relate to drug dose and concentration at a target site Pharmacotherapy is the use of drugs to treat disease Requires knowledge of drugs, physiology, and pathology (this course will teach you some of each of these but none can be covered in depth) Effect Log Dose 7

Important “pharmaco” terminology Pharmacoepidemiology investigates the effects of drugs on populations Pharmacoeconomics examines the cost-effectiveness of drug treatments Pharmacogenetics and pharmacogenomics study the influence of genetic variation on pharmacodynamic and pharmacokinetic properties of drugs 8

The Two Key Aspects of Pharmacology: Pharmacokinetics and Pharmacodynamics Drug Pharmacokinetics Intended target Unintended targets Toxicokinetics Doesn’t show elimination! Pharmacodynamics Therapeutic effects Toxicodynamics Toxic effects 9

The Two Key Aspects of Pharmacology: Pharmacokinetics and Pharmacodynamics Drug administration Effector sites Distribution Pharmacodynamics Excretion Metabolism Pharmacokinetics 10

Pharmacokinetics and Pharmacodynamics: A More Complete Schema Interaction with cellular targets is the focus of most research regarding drug action (“Molecular pharmacology”) and includes studies of receptors, receptor signaling, and post-receptor responses 11

Prescribing/dispensing/administering the wrong drug (or wrong dose) How do drug efficacy and toxicity contribute to therapeutic success, therapeutic failures, and medical errors? The major goal is rational therapeutics: Rational therapeutics seeks to maximize therapeutic responses while minimizing therapeutic failures and medical errors that occur because of “therapeutic wrongs”: Knowing, understanding, and implementing general principles and specific facts about classes of drugs and individual drugs Prescribing/dispensing/administering the wrong drug (or wrong dose) To the wrong patient At the wrong time 12

What is the “therapeutic partnership”? Patients and health providers (e.g., physicians and pharmacists) are partners that seek to optimize drug prescription/dispensing/administration and thereby maximize efficacy and minimize toxicity, thus increasing the “therapeutic window” (between beneficial and toxic effects). Adherence (compliance) to drug regimens is a major problem in therapeutics: many patients do not take the correct drug/dose at the correct time/frequency for the correct period of time). Thus, new approaches are needed to solve this problem and will likely include : Simplification of medication regimens Patient/caregiver education Ongoing assessment of adherence and outcomes Novel formulations, delivery methods, monitoring/assessment 13

[Drug] in Blood and Relation to Effects Therapeutic Window [Drug] in Blood and Relation to Effects [Drug] in blood Oertel, W. et al. Neurology 2007;69:S4-S9 Note the need to achieve effective concentration (efficacy) without exceeding levels that increase side effects (toxicity) 14

Relationship between Rx and Tx Doses Therapeutic Window: Relationship between Rx and Tx Doses Rx effect Tx effect Rx effect Tx effect Effect Effect Log Dose Log Dose For our last topic, do a few problems involving d-r relationships Potency: EC50 Rx effect Tx effect Effect Rx effect = Therapeutic effect Tx effect = Toxic effect Log Dose 15

What are some major principles of pharmacotherapy? Use of scientific method and application of fundamental principles must guide drug prescription/administration and the monitoring/evaluation of drug administration Since there are few “magic bullets”, it is critically important for those who prescribe, dispense and administer drugs to be knowledgeable and those who discover drugs must seek to optimize efficacy and minimize toxicity Each patient’s prescription is a scientific experiment (but is not usually thought of in this way): Hypothesisdrug treatmentassessment of outcomeinterpretation?make changes for next experiment 16

Can one achieve selectivity in pharmacotherapy? Drugs are “selective” (rarely “specific”) in their sites of action Selectivity depends on several factors Chemical nature of drug Dose and route of administration Patient characteristics (e.g., genetics, age, gender, co-existing disease) Selective toxicity for drugs used as chemotherapeutic (antimicrobial, anticancer) agents or pesticides (e.g.,insecticides) that kill targets without harming the host Difficult to achieve selective toxicity if the “target” resembles the host Risk-benefit ratio describes adverse vs. beneficial effects of a drug; acceptable risk/benefit ratios depend on: Severity of the disease being treated (or prevented) Economic and societal factors: many new drugs are VERY expensive and raise concerns about “rationed care” that will only be available for the world’s most wealthy citizens: is this “moral”? 17

A worldwide problem of overuse of drugs: Antibiotic usage can enhance microbial resistance and ultimately, lead to failure of treatment 18

Where does one obtain reliable information about drugs? Textbooks of pharmacology (but most have “dated” info even at time of publication): Recommended text is this course provides a good overview on topics that will be covered Journals and especially from on-line sources that provide regular updates Clinical Pharmacology (Online Clinical Library @ BML) Micromedex (Online Clinical Library @ BML) The Medical Letter (E-Journals @ BML) Physician’s Desk Reference (PDR) Drug company-generated compilation of FDA-approved package inserts + pictures of drugs 19

Can drug therapy be individualized/personalized? Much current interest in the individualization of drug therapy and taking into account genetic and environmental factors There has been some success but progress toward individualized therapy has been slow—especially as related to drug action Many key questions remain, including: Are the most important inter-individual differences in pharmacokinetics or pharmacodynamics? Will knowing a person’s genome improve the choice among and dosing of drugs? Will/should clinical trials be “genomically stratified” such that drugs are tested and then approved for genomic sub-populations? Should basic research studies emphasize such issues during drug development? Bottom line: This is a work in progress that will likely drive research and changes in drug approval and prescribing 22

What new efforts in pharmacotherapy and pharmacology are on the horizon? In addition to “genetically informed” understanding of disease, drug development/prescribing, other aspects of pharmacotherapy that will likely change are: ”New” disease/drug targets based on evolving information from genetic, biochemical, molecular biological, and imaging studies [as will be discussed in this course] New formulations with an increased number of “biological drugs” (e.g., antibodies, binding proteins, ?antisense, ?siRNA, ?gene therapy) Alternative methods of drug delivery (less pain and other side effects, better/more consistent delivery and bioavailability) Less-invasive but increased assessment of efficacy and toxicity Better methods and their wider use to assess compliance/adherence Efforts to create errorless drug prescribing/administration—these are a major source of medical errors, which in spite of much publicity are still seen as a serious, unsolved problem 23

How are drugs developed and approved? Answer: Following discovery of new chemical entities (NCEs) in academia or industry, studies are conducted in animals and humans. Randomized, placebo-controlled, double-blind clinical trials are the gold standard for demonstration of efficacy and determining benefit/harm..

Drug discovery and approval: Preclinical research and Phases 1-4

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