MUSTAFEEZ BABAR.  General Principles of Pharmacology  Basic Pharmacology  Clinical Pharmacology-(Selected Organ systems)  Molecular Basis of Pharmacology.

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  • General Principles of Pharmacology Basic Pharmacology Clinical Pharmacology-(Selected Organ systems) Molecular Basis of Pharmacology Pharmacological Parameters and Calculations for drug candidate selection
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  • Sessionals = (15+5)*2 Assignment/ presentation = 10 Terminal = 50
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  • 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
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  • 1. What is pharmacology? 2. Why are drugs important for human health and scientific research? 3. How do drug efficacy and toxicity contribute to therapeutic success, therapeutic failures and medical errors ? 4. What is the therapeutic partnership? 5. What are some major principles of pharmacotherapy? 6. Where does one obtain reliable information about drugs? 7. Can drug therapy be individualized/personalized? 8. What new efforts in pharmacotherapy and pharmacology are on the horizon? 9. How are drugs developed and approved? 2
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  • 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?
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  • 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 MDs do and drugs are the raison detre of pharmacists. 4 Understanding the principles of pharmacology is thus central to the efforts of MDs, PharmDs and most biomedical researchers
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  • 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 insightsin 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
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  • The search for magic bulletsagents 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
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  • 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) Log Dose Effect 7
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  • 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 Important pharmaco terminology 8
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  • Pharmacokinetics Drug Intended target Unintended targets Therapeutic effects Toxic effects Pharmacodynamics The Two Key Aspects of Pharmacology: Pharmacokinetics and Pharmacodynamics 9 Toxicodynamics Toxicokinetics
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  • Pharmacokinetics Drug administration Distribution Effector sites Pharmacodynamics ExcretionMetabolism The Two Key Aspects of Pharmacology: Pharmacokinetics and Pharmacodynamics 10
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  • Pharmacokinetics and Pharmacodynamics: A More Complete Schema 11 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
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  • 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 : 12 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
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  • 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
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  • Oertel, W. et al. Neurology 2007;69:S4-S9 Therapeutic Window 14 [Drug] in Blood and Relation to Effects [Drug] in blood Note the need to achieve effective concentration (efficacy) without exceeding levels that increase side effects (toxicity)
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  • Log Dose Effect Rx effectTx effect Log Dose Effect Rx effectTx effect Log Dose Effect Rx effectTx effect Therapeutic Window: Relationship between Rx and Tx Doses 15 Rx effect = Therapeutic effect Tx effect = Toxic effect
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  • 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 16 Each patients 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
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  • 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 worlds most wealthy citizens: is this moral? 17
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  • A worldwide problem of overuse of drugs: Antibiotic usage can enhance microbial resistance and ultimately, lead to failure of treatment 18
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  • 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) Physicians Desk Reference (PDR) Drug company-generated compilation of FDA-approved package inserts + pictures of drugs 19
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  • 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 slowespecially as related to drug action Many key questions remain, including: Are the most important inter-individual differences in pharmacokinetics or pharmacodynamics? Will knowing a persons 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? 22 Bottom line : This is a work in progress that will likely drive research and changes in drug approval and prescribing
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  • 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/administrationthese are a major source of medical errors, which in spite of much publicity are still seen as a serious, unsolved problem 23
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  • 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..
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