General Pharmacology Lecture Notes (PDF)

GENERAL PHARMACOLOGY LECTURE INTRODUCTION Pharmacology is the science of drugs (Greek: Pharmacon—drug; logos— discourse in) A drug is any single chemical substance that can produce a biological response. Pharmacology can be defined as the study of substances that interact with...

GENERAL PHARMACOLOGY LECTURE INTRODUCTION Pharmacology is the science of drugs (Greek: Pharmacon—drug; logos— discourse in) A drug is any single chemical substance that can produce a biological response. Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. INTRODUCTION Pharmacology as an experimental science was ushered by Rudolf Buchheim who founded the first institute of pharmacology in 1847 in Germany. In the later part of the 19th century, Oswald Schmiedeberg, regarded as the ‘father of pharmacology’, together with his many disciples like J Langley, T Frazer, P Ehrlich, AJ Clark, JJ Abe fundamental concepts in pharmacology. INTRODUCTION DRUG DEVELOPMENT AND REGULATION The sale and use of drugs are regulated in almost all countries by governmental agencies. In the United States, regulation is by the Food and Drug Administration (FDA). Before a new drug can be approved for regular therapeutic use in humans, a series of animal and experimental human studies (clinical trials) must be carried out DRUG DEVELOPMENT AND REGULATION New drugs may result from the screening of hundreds of compounds against model diseases in animals. Because society expects prescription drugs to be safe and effective, governments regulate the development and marketing of new drugs. Current regulations in the USA require evidence of relative safety (derived from acute and subacute toxicity testing in animals) and probable therapeutic action (from the pharmacologic profile in animals) before human testing is permitted. SAFETY AND EFFICACY Efficacy is the capacity to produce an effect (eg, lower blood pressure). Effectiveness differs from efficacy in that it takes into account how well a drug works in real-world use Drug safety is the science of detection, assessment, understanding and prevention of side effects which allows us to understand more about the risks and benefits of a medicine Often, a drug that is efficacious in clinical trials is not very effective in actual use. DRUG DEVELOPMENT AND REGULATION ANIMAL TESTING The animal testing of a specific drug that is required before human studies can begin is a function of its proposed use and the urgency of the application. Because of the urgent need, anticancer drugs and anti-HIV drugs require less evidence of safety than do drugs used in treatment of less threatening diseases. Urgently needed drugs are often investigated and approved on an accelerated schedule ANIMAL TESTING ACUTE TOXICITY Acute toxicity studies are required for all new drugs. These studies involve administration of incrementing doses of the agent up to the lethal level in at least 2 species. SUBACUTE AND CHRONIC TOXICITY Subacute and chronic toxicity testing is required for most agents, especially those intended for chronic use. Tests are usually conducted for 2–4 weeks (subacute) and 6–24 months (chronic), in at least 2 species TYPES OF ANIMAL TESTS A. Pharmacologic Profile The pharmacologic profile is a description of all the pharmacologic effects of a drug (eg, effects on cardiovascular function, gastrointestinal activity, respiration, hepatic and renal function, endocrine function, CNS). B. Reproductive Toxicity Reproductive toxicity testing involves the study of the fertility effects of the candidate drug and its teratogenic and mutagenic toxicity. TYPES OF ANIMAL TESTS TYPES OF ANIMAL TESTS C. Carcinogenesis Carcinogenesis is the induction of malignant characteristics in cells. It is difficult and expensive to study The Ames test is often used to screen chemicals because there is a moderately high degree of correlation between mutagenicity in the Ames test and carcinogenicity in some animal tests. The Ames test, the standard in vitro test for mutagenicity, uses a special strain of salmonella bacteria that depends on specific nutrients in the culture medium. CLINICAL TRIALS Approval by institutional committees that monitor the ethical (informed consent, patient safety) and scientific aspects (study design, statistical power) of the proposed tests is required for human testing of a new drug to be carried out. The manufacturer submits an Investigational New Drug application (IND) to the FDA to obtain authorization to administer an investigational drug or biologic product to humans. Clinical studies are of ten conducted to collect safety and effectiveness information in support of marketing applications for biologic and drug products CLINICAL TRIALS The major clinical testing process is usually divided into 3 phases that are carried out to provide information for a New Drug Application (NDA). A fourth phase of study (the surveillance phase) follows NDA approval. PHASE I CLINICAL TRIAL Consists of careful evaluation of the dose-response relationship and the pharmacokinetics of the new drug in a small number of normal human volunteers (eg, 20–100). An exception is the phase 1 trials of cancer chemotherapeutic agents and other highly toxic drugs; These are carried out by administering the agents to volunteer patients with the target disease. PHASE I CLINICAL TRIAL In this phase, the acute effects of the agent are studied over a broad range of dosages, Starting with one that produces no detectable effect and progressing to one that produces either a significant physiologic response or a very minor toxic effect PHASE II CLINICAL TRIAL This involves evaluation of a drug in a moderate number of sick patients (eg, 100–200) with the target disease. A placebo or positive control drug is included in a single-blind or double- blind design. The study is carried out under very carefully controlled conditions, and patients are closely monitored, often in a hospital research ward. The goal is to determine whether the agent has the desired efficacy (ie, produces adequate therapeutic response) at doses that are tolerated by sick patients. PHASE III CLINICAL TRIALS This involves many patients (eg, 1000–6000 or more, in many centers) and many clinicians who are using the drug in the manner proposed for its ultimate general use (eg, in outpatients). Such studies usually include placebo and positive controls in a double-blind crossover design. PHASE III CLINICAL TRIALS The goals are to explore further, the spectrum of beneficial actions of the new drug, to compare it with placebo (negative control) and older therapy (positive control), and to discover toxicities, if any, that occur so infrequently as to be undetectable in phase 2 studies If the drug successfully completes phase 3, an NDA is submitted to the FDA. If the NDA is approved, the drug can be marketed and phase 4 begins. PHASE IV CLINICAL TRIALS This represents the post marketing surveillance phase of evaluation, in which it is hoped that toxicities that occur very infrequently will be detected and reported early enough to prevent major therapeutic disasters. Manufacturers are required to inform the FDA at regular intervals of all reported untoward drug reactions. THE NATURE OF DRUGS Drugs in common use include inorganic ions, nonpeptide organic molecules, small peptides and proteins, nucleic acids, lipids, and carbohydrates. Many drugs found in nature are alkaloids, which are molecules that have a basic pH in solution, usually as a result of amine groups in their structure. THE NATURE OF DRUGS A. Size and Molecular Weight Drugs vary in size from molecular weight (MW) 7 (lithium) to over MW 50,000 (thrombolytic enzymes, antibodies, other proteins). Most drugs, however, have MWs between 100 and 1000. Drugs smaller than MW 100 are rarely sufficiently selective in their actions, whereas drugs much larger than MW 1000 are often poorly absorbed and poorly distributed in the body. THE NATURE OF DRUGS B. Drug-Receptor Bonds Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker electrostatic bonds (eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds). PHARMACODYNAMICS