Pharmacology. ▫ Basic Principles. ○ Study of drugs. ○ Actions. ○ Dosage. ○ Therapeutic uses. (indications). ○ Adverse effects. Cholinergic Pharmacology. Case: Anticholinesterase (PDF). Harold Demonaco. Prof. Gary Strichartz. Course Faculty. 4. Drug Metabolism. Pharmacogenetics. Basic Concepts of Pharmacology in Drug. Development. Bob Lyon, PhD. Procter and Gamble Healthcare. Mason, OH. American Translators.
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PDF | IntroductionThe nature of drugsMechanisms of drug actionDrug potencyThe role of pharmacodynamics in determining variability of drug. Principles of Pharmacology is intended as a concise reference book for Download the PDF to view the article, as well as its associated figures and tables. Title: Principles o pharmacology: the pathophysiologic basis o drug therapy / David E. Golan, editor in chie ; Ehrin J. Armstrong, April W. Armstrong, associate .
This comparison is important so that a thorough benefit - risk analysis can be made before proceeding to test the medicine in clinical human studies. If the medicine does proceed to the clinical phase , data gathered during non- clinical pharmacology and toxicology studies help to determine the dosage of medicine given to volunteers in the first clinical studies first-in-human. Pharmacology is divided into two key areas: pharmacokinetics and pharmacodynamics. These are explained in more detail below. Pharmacokinetics Pharmacokinetics PK is the study of the effect the body has on a medicine. The acronym you will find in every textbook associated with pharmacokinetics is ADME: Absorption: How the medicine gets in to the body Distribution: Where the medicine goes in the body Metabolism: How the body chemically modifies the medicine Excretion: How the body eliminates the medicine ADME The key principles of Pharmacokinetics — the study of the effect the body has on a medicine — are represented in the acronym ADME.
This is a particular problem for rare but potentially lethal adverse drug effects.
Furthermore, to interject into this discourse, we noted earlier that Safety Pharmacology as exists today is tasked with identifying drugs as unsafe within the therapeutic window so, in effect, the data set the company presents to regulators is a failure to disprove that the drug is likely to be unsafe, rather than positive indication of likely safety.
Thus, we really remain years away from being able to take a drug's range of IC50 values for different molecular targets that is, its selectivity profile and generate a number that reflects its risk that is, liability to evoke TdP that can then be balanced against a number that reflects its likely therapeutic benefit. This model applies to all and any rare, but potentially lethal, adverse effect issues. So, how has this impacted on the unfolding and evolving history of Safety Pharmacology?
In the absence of quantification of the predictive value of tests and programmes, industry and the regulators have attempted to accommodate one another through a series of industry- and regulatory-led initiatives. The ICH is a project started in that utilizes the regulatory authorities of the United States, Europe and Japan in conjunction with experts from the pharmaceutical industry from the three regulatory regions to discuss scientific and technical aspects of therapeutic drug registration Bass et al.
What has this to do with pharmacology? The answer is that Safety Pharmacology has been shaped in structure and function by this ongoing accommodation between pharmacologists and regulatory authorities.
Thus, it is important to consider who the regulators are and what they want to know. Thus it is primarily designed to take account of regulatory requirements; scientific issues are secondary.
Follow-up studies may be triggered if there is a need to characterize specific adverse effects found in initial Safety Pharmacology studies. Although follow-up may appear more scientifically driven than the core programme, the design of follow-up studies is nevertheless based on what is perceived by the pharmaceutical company to be the data required by the regulators.
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Need help getting started? The vigilant post-marketing surveillance PMS efforts by regulatory authorities necessary to confirm the existence of a rare adverse event occur after approval for human use.
The SRS receives adverse drug reaction reports derived from health care providers and hospitals. When an adverse effect is very rare, it may require millions of prescriptions before an awareness of its existence emerges. There are numerous examples of this in the literature for example, Kemp, ; one of the best is terfenadine. In the mid s the antihistamine, terfenadine Seldane, Marion Merrell Dow , was withdrawn following a growing awareness that the drug could evoke the potentially life threatening cardiac syndrome, torsades de pointes TdP , in otherwise healthy patients Monahan et al.
The problem here was that terfenadine, a non-cardiovascular drug, had low efficacy to evoke TdP making it so rare an event that it required several million prescriptions before its liability became suspected. The other important consideration here is that the indication for which terfenadine was used hayfever is itself far from life threatening. This episode was of great importance to what we now call Safety Pharmacology a discipline that did not exist at the time.
This is because predicting terfenadine's TdP risk was not possible by the conventional preclinical toxicity testing methods conducted at the time.
Preclinical toxicology testing, as an approach involved determining the high-dose adverse event profile of a compound given at chronic, toxic doses, but would not have detected a rare lethal event liability at therapeutic dosage.
Indeed, screening for TdP liability risk in animals or in phase 1 and 2 clinical investigations whether by evaluating QT prolongation or by exploring other putative biomarkers was not recognized as relevant, let alone necessary, in the late s and early s.
Moreover, the magnitude of the effect of terfenadine on QT interval is small, and peak effects may exhibit a delayed onset Ollerstam et al. This problem could have been avoided if, instead of routine toxicology, a programme of specific high throughput screening HTS for TdP liability had been utilized in early drug discovery at the time, but consideration of biomarkers for rare adverse event liability was not part of the toxicology agenda in the early s.