An error occurred while setting your user cookie. Please set your. browser to accept cookies to continue. This cookie stores just a. ID; no other information is captured. Accepting the NEJM cookie is. SlimFast Success Stories. We’ve been helping people reach their goals for 40 years with a plan that is proven to work. Get inspired by real men and women who have. Directions For Combat Powder: Mix 1 scoop of COMBAT PROTEIN POWDER® with 8–12. Vary the amount of water to achieve desired consistency and taste. Indications contra-indications dosage side-effects pregnancy overdose identification patient information one-alpha® capsules 1 µg. A diet for healing chronic disease, restoring youthful vitality, and achieving long life. 2 235 oxidation under sedentary conditions than the con-trol group after test beverage ingestion. On the other hand, in the catechin group, the fat oxidation in the. 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Explain what is meant by additive and synergistic drug effects. Define the terms ED5. LD5. 0, TD5. 0 and Therapeutic Index. You are expected to have read this handout and completed the online Canvas Med Pharm quiz by 3 AM before the day of this class session. Bring your “clickers” with you to class. DEFINITIONSPharmacology - is the science of the interaction of chemical agents (drugs) with living systems. Drug - a substance (chemical agent) that affects a biological system in a potentially useful way. EC5. 0: the drug concentration producing 5. ED - Effective Dose (e. ED5. 0: the drug dose producing 5. Which definition is appropriate depends on the context in which the abbreviation is being applied; i. TD5. 0: the dose producing a toxic effect in 5. LD - Lethal Dose (e. LD5. 0: the dose producing a lethal effect in 5. LD values almost always refer to animal studies, since lethal doses in humans are rarely known with any accuracy. Two Primary Branches of Pharmacology. The two major branches of pharmacology are: pharmacodynamics and pharmacokinetics. The mechanism of action can typically be described in biochemical or molecular terms. Clinical Pharmacology and Therapeutics. This discipline is interested in characterizing the Indications and therapeutic uses of drugs- Emphasis is placed on the therapeutic use of drugs for the treatment of disease in the clinical years with clinical pharmacology, internal medicine and therapeutics. Toxicology. The aspect of pharmacology that deals with the adverse effects of drugs. S (- ) Carvedilol binds to both . Differences in drug potency are evaluated by comparing EC5. The two major branches of pharmacology are: pharmacodynamics and pharmacokinetics. Pharmacodynamics - The study of the relationship between concentrations of drug and. ED5. 0) values. Differences in drug efficacy are evaluated by comparing differences in maximal response at high drug doses or concentrations. In contrast, full agonists produce a full or maximal response. In figure 3, Drug A is a full agonist, and Drugs B, C & D are partial agonists. The drug which can produce an effect at lower drug concentrations is “more potent” (in Figure 2, Drug A is the most potent, and Drug D is the least potent). Drugs B, C & D) are referred to as partial agonists. Drug A has a relative efficacy that is 2 times than Drug C, and ~1. Drug D. Clinical Examples of Partial Agonists. Clinically used examples of partial agonists include. Aripiprazole (Abilify . Schizophrenia is a condition associated with both excess dopamine activity in one area of the brain (resulting in hallucinations and delusions), as well as a co- existing reduced dopamine activity in another area (causing cognitive impairment). Aripiprazole is thought to produce beneficial effects in schizophrenia by exerting agonist effects in areas of dopamine deficit, while exerting sufficient antagonist effects in areas of dopamine hyperactivity. Buprenorphine (Suboxone . Acebutolol, penbutolol & pindolol are “beta blockers” that have additional “intrinsic sympathomimetic activity” (ISA), which is a different way of saying they behave as partial agonists at . The presence of ISA results in a neutral effect on heart rate and cardiac output when the sympathetic nervous system is not activated (e. These drugs have been shown to be effective and relatively safe, but the issue of whether their “ISA” constitutes a therapeutically significant advantage over pure receptor antagonism is still being debated (Frishman & Saunders, 2. They may be an appropriate choice for patients who require a beta blocker (e. They are generally considered undesirable for use in patients who have previously had an myocardial infarction, since this may interfere with their otherwise anti- ischemic properties on the heart. Signal Transduction Mechanisms for Agonists. Once an agonist has bound to its receptor, its effects are transduced into a cellular response by one of several different mechanisms. Examples of these mechanisms are shown below. Binding of the drug to the receptor site(s) results in a conformational change in the receptor/channel complex that typically causes the ion channel to open. Na and K for nicotinic receptors) down their electrochemical gradient with a resultant change in membrane potential (Figure 4). Binding of 2 molecules of acetylcholine to the nicotinic receptor/channel complex causes the channel to open. Either the alpha or beta/gamma subunits stimulate the channel to open. Binding of an agonist to the m. G- protein (Gi) which in turn stimulates a K- selective channel to open. One involves the G- protein (Gs) mediated activation of adenylyl cyclase, with subsequent formation of camp and activation of protein kinase A (PK- A) (Figure 6). Norepinephrine binding to beta. AC), which converts ATP to c. AMP. Angiotensin II binding to AT1 receptors activates phospholipase C (PLC). Tyrosine Kinases). This class of receptors mediates the first steps in the transduction of signals carried by insulin and a wide variety of growth factors such as epidermal growth factor (EGF), atrial natriuretic factor (ANF) and transforming growth factor beta (TGF- . The interaction between receptors causes the tyrosine kinases to become active, resulting in auto- phosphorylation of the enzyme domains, and phosphorylation of tyrosine residues on different downstream signaling proteins (S. Noncompetitive Antagonists. Antagonists are drugs that bind to receptors (have affinity), but do not produce a substantial degree of receptor stimulation (they have very low efficacy). The vast majority of clinically used drugs that act as receptor antagonists are competitive antagonists. Noncompetitive antagonists either bind irreversibly (e. Competitive Antagonism, where both the agonist (Isoproterenol) and the antagonist (Propranolol) bind reversibly to the same receptor subtype (. Non- competitive antagonism. This results in a tonic level of stimulation of downstream events, such as stimulation of adenylate cyclase. However, in addition, the binding of the reverse agonist to the receptor alters the receptor conformation in such a way as to decrease its interaction with G- proteins, resulting in a decrease in basal stimulation of G- proteins and a reduction in the activity of adenylate cyclase. Acetylcholine and norepinephrine exert their effects through different receptors and signal transduction pathways, which when activated produced opposing effects (e. They therefore “physiologically” antagonize each others effects without interacting with the same receptors. Chemical antagonism occurs when a drug reduces the concentration of an agonist by forming a chemical complex (e. Example: protamine sulfate is a positively charged substance that when given i. As a result, protamine sulfate administration is a type of “antidote” for heparin overdose, because once heparin binds to protamine sulfate, it cannot exert its anticoagulant effects. Pharmacokinetic antagonism occurs when one drug accelerates the metabolism or elimination of another (e. Drugs often work on multiple receptors. Drugs often work on more than one receptor, and as a result produce more than one kind of biological response (Figure 1. Each receptor subtype selectively interacts with different G proteins & thus activate different intracellular messenger pathways, resulting in different biological responses. Selectivity, and the Therapeutic Window. If a drug has one effect, and only one effect on all biological systems it possesses the property of specificity. Hence when studying drug effects in vitro, one can most commonly compare drug effects to drug concentrations and a concentration producing 5. EC5. 0) can be defined. An example of an exception to this rule is when one is using an impure source of a drug (e. John’s wort – a herbal medication containing a mixture of active ingredients, with varying purity between preparations). In this case the total dose (gram weight) of St. John's wort used would be more easily defined vs the concentration of the active ingredient(s), which may be unknown. The concentration of drug achieved in the bloodstream (e. As a result, in whole animal experiments, we talk of doses that produce a given magnitude of therapeutic effect, e. ED5. 0 (and not EC5. These studies typically involve giving a range of doses to a large population of animals/patients and measuring an all- or- none type of “quantal” response (such as – does this dose produce vomiting, or prevent hiccups within a 1 hour time period). In this situation, one can define the minimum dose needed to produce the desired effect in each animal or patient. The results of this type of study can be plotted in the form of a quantal dose response curve (Figure 1. In a population study, the dose that produces the desired effect in 5. ED5. 0 or ED5. 0. To summarize, ED5. The key to understanding the meaning of the term “ED5. If ED5. 0 is being used to describe drug effects in an individual subject, ED5. In contrast, if the discussion concerns drug responses in a population, ED5. Compare what is represented on the y- axis of Figure 1. Figures 2 & 3. The results have been plotted as a histogram, and fit with a gaussian curve. The reason this index is less commonly used is because the LD1 value, at least for human populations, is typically unknown or poorly defined, for ethical reasons! Figure 1. 3. The relationship between the dose- response relationships for producing therapeutic and toxic side effects. Examples of physiological, chemical and pharmacokinetic antagonism were discussed above (page 8). Two common types of “agonistic” drug interactions are additive or synergistic interactions. An additional (graphical illustration) of additive and synergistic effects is shown in Figure 1. Synergistic effects. Following an initial response (such as cellular accumulation of c.
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