RXRS-402 Lecture Notes.pdf

Week 1: What is pharmacology: Pharmacology is the science that describes the interaction of chemicals with living systems at all levels. ○ Pharmacology deals with the fate and actions of drugs in the body. Pharmakon – drug or poison...

Week 1: What is pharmacology: Pharmacology is the science that describes the interaction of chemicals with living systems at all levels. ○ Pharmacology deals with the fate and actions of drugs in the body. Pharmakon – drug or poison Logos – word or discourse (the science of) Pharmacology overlaps with pharmacy (the science of the preparation of drugs) and therapeutics (the treatment of disease with drugs and by other means) Pharmacokinetics (PK): What happens to drugs once in the body. Investigates the effects of the biological system on drugs (absorption, distribution, elimination...) Pharmacodynamics (PD): How drugs alter disease. Describes the fundamental action of a drug on a physiological, biochemical or molecular level. Toxicology: How drugs can potentially damage the body–the undesirable effects of chemicals on living systems. Includes poisons, antidotes and unwanted side effects of drugs Pharmacotherapeutics: The use of prescription and over-the counter drugs to prevent and treat diseases Pharmacogenomics: Examines the effects of genetic factors to variations in the drug response (“Asian Flush”, Codeine “resistance”) Pharmacy: is the art of preparing, compounding and dispensing chemicals for medicinal use. Definitions: Prophylactic refers to a drug or procedure aimed to prevent disease Palliative refers to a drug or procedure aimed to relieve symptoms Therapeutic refers to a drug or procedure aimed to treat a disease Tolerance is the increased resistance to the usual effects of an established dose of a particular drug Effective dose (ED50) is the concentration at which 50% of the subjects show a predefined response Efficacy refers to the maximum effect a drug can produce regardless of the dose. It is a measure of how well a drug can produce a therapeutic response. Potency Refers to the amount of drug required to produce a particular effect and is often compared by looking at the dose-response curves of different drugs. Potency does not indicate how well a drug will work, only the amount needed to produce an effect. ○ e.g. Drug A requires fewer milligrams than Drug B to achieve the same pharmacological response ○ Drug A has the higher potency, yet, both drugs have the same efficacy. Graphical Depictions of Potency vs Efficacy Drugs A & B clearly have similar higher efficacy than drug C. Drug A is significantly more potent than drug B. Drug C has lower potency and efficacy compared to A and B Agonist/Antagonist: Agonist: Activator ○ Specific ligand for receptor mediated response (EC50)  ○ Partial agonist: less than 100% activation when receptors fully occupied ○ Inverse Agonist: Produce response below the baseline response measured in absence of drug. Antagonist: Inhibitor ○ Specific inhibitor of receptor mediated response (IC50) Median Effective Dose: It is possible to evaluate doses to which 20%, 70% or 84% or any other percentage of patients will respond. Such effective doses are described as ED20, ED70 or ED84. The mean effective dose is the ED50. When drugs have parallel LDR curves, their potencies can be compared, and the more potent drug has a lower ED 50. ○ Quantal log dose-response curve: The LDR is a simple way to determine the ED50 (the effective dose, 50%) ADME(T): Significant cause of attrition Toxic Dose: dose at which drug causes toxicity in 50% (LD50) of patients Effective Dose: dose at which drug cause response in 50% (ED50) TD50/ED50 = Therapeutic Index (TI) Drug Classifications: Natural Preparations (galenicals or ethanol tinctures) are relatively crude preparations obtained by drying or extracting plant or animal materials (e.g., digitalis and desiccated thyroid). These may date back to prehistoric times. Pure Compounds are isolated from natural sources by physical and chemical extraction and purification. Morphine was the first of these, purified in 1805. Modern examples include penicillin from molds and anticancer drugs (e.g., vinblastine and vincristine) Semisynthetic compounds are obtained by chemical modification of pure compounds obtained from natural sources. For example, acetylating two hydroxyl groups of morphine yields diacetylmorphine (heroin) and changing a side group of penicillin yields oxacillin. Semisynthetic compounds are made in the hope they will yield major improvements of the parent compound with respect to potency, specificity and duration of action. Purely synthetic compounds are the most recently developed class of drugs. Many of these compounds are developed for other purposes and their medical uses were discovered accidentally  (eg. disulfiram, barbiturates, benzodiazepines). Others were synthesized based on knowledge gained from semisynthetic compounds, resulting in custom-designed molecules. Apart from classifying drugs by origin, they may also be classified based on use; i.e., based on which organs systems they primarily affect or to what uses they are put. Examples include antibiotics, diuretics, cardiac glycosides, anticonvulsants. How are humans exposed to drugs? Medical Prescriptions Over-the-counter sales (cough remedies, analgesics) Nonmedical use (alcohol, tobacco, illicit drugs) Industrial use (solvents, flavorings, colorings, fillers) Agricultural use (insecticides, herbicides) Accident (aflatoxin on peanuts, ergot on rye) or intentional dosing (homicide, suicide). Most societies control the availability, quality and permitted uses of drugs. Pharmacokinetics: What does the body do to the drug and why is that important? The quantitative description of the rates of the various steps of drug disposition, including: 1. absorption of drugs 2. distribution to organs and tissues 3. elimination by biotransformation and excretion It allows pharmacologists to characterize in detail the fates of drugs in the body and to identify factors that determine these fates. Allows physicians to calculate dosing regimens (route, dose, frequency of drug administration). Relations among dose, plasma drug concentration and drug effect: 1. Dosage 2. Free drug concentration in plasma water 3. Free drug concentration at site of action 4. Intensity of effect The duration of drug effects is generally related to the duration of the drug’s presence at the site of action. Pharmacokinetics concerns itself with models of the fates of drugs in the body. These models require verification by experimental observation. Administration - Getting the drug in: Route of drug administration determines how quickly a drug reaches its sites of action ○ Oral – tablet/syrup ○ Sublingual – tongue ○ Inhaled – via lungs ○ Parental – IV/injected ○ Topical – ointment ○ Transdermal – Patch ○ Rectal/Vaginal Goal of drug administration: get an adequate (but not toxic) concentration of drug to the necessary site of action.  As quickly as possible to maintain that concentration as continuously and evenly as possible Commonly used routes of drug administration. IV = intravenous; IM = intramuscular; SC = subcutaneous. Route of drug administration determines how quickly a drug reaches its sites of action. The plasma concentrations of a drug are quite different depending on the route of administration. ADME: Absorption (drug in plasma), distribution (Drug in tissues), metabolism (Metabolite(s) in tissues), Excretion. Absorption: What affects absorption: ○ Drug properties–solubility, size, structure, ionizability, disintegration, dissolution, concentration, salt form, etc. ○ More SA = more absorption ○ Conditions of surface: pH of environment, digestive enzymes, flora and fauna, transporters, etc. Distribution: Metabolism: The first pass effect: The first-pass effect is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. This occurs via the liver. First pass metabolism is why oral administration not as effective as other routes Prepare substances to be eliminated (biotransformation):  ○ Enzymes in liver regulate metabolism ○ Lots of inter-individual variation in liver enzyme activity ○ CYP450-major metabolize Liver Functions: Detoxification of drugs and toxins Formation of bile (required for absorption of fats and fat-soluble vitamins) Manufacture of plasma proteins (albumin & blood clotting proteins) Urea formation (from ammonia and CO2) Metabolism of carbohydrates (glycolysis) and cholesterol (eg. VLDL) Excretion: Kidney (urine): ○ Remove body wastes and water soluble toxins ○ Maintain water and electrolyte balance ○ Maintain acid/base balance ○ Endocrine functions Irenin, renal erythropoietic factor). Liver (end product fecal matter), process involves Cyt P450 Pharmacodynamics - What impact does the drug have on the patient: Pharmacodynamic changes: Alterations in receptor levels may change: For example, beta-blockers are less effective in the elderly patients. Age-related changes resulting in sensitivity to certain classes of drugs place the elderly at risk for adverse drug reactions CNS depressants (e.g., benzodiazepines) resulting in delirium, confusion, agitation and sedation Anticoagulants and hemorrhage e.g., in combination with NSAIDs, salicylates. Alpha-blockers resulting in orthostatic hypotension Anticholinergic medications resulting in dry mouth, constipation, urinary retention, blurred vision, confusion Receptor mediated drug action: Recognition sites: ○ Recognize with great selectivity/specificity ○ Bind with high affinity (EC50 = uM to nM) Effector: ○ Signal generation ○ Transduction of binding signal ○ Mechanism based on conformational change of the receptor → change in function Amplification: ○ Ion transport ○ Enzyme activation/deactivation ○ Protein synthesis Specificity of drug action: No Drug is entirely specific in the sense that it acts exclusively only on one type of cell or tissue, having just the desired effect and no other.  Drugs cary in their specificities and the usefulness of a drug clinically is often directly related to its specificity Poison: a compound which has deleterious effects on cell function without therapeutic effects ○ e.g. cyanide combines strongly with the Fe3+ found in many proteins interfering in their functioning. Some drugs have absolutely no toxicity in concentrations used clinically ○ E.g. penicillin inhibits a bacterial enzyme involved in the formulation of bacterial cell walls. Humans, lacking cell walls, are unaffected by these concentrations of penicillin. In between these two extremes (cyanide and penicillin) are many drugs that are used clinically Generally, the useful, therapeutic effects of drugs may be separable from the toxic effects based on differences in ○ Their respective mechanisms of action ○ Their dose-response relationships if their mechanisms of action are similar ○ The sites at twitch therapeutic and toxic effects are produced Attempts to increase the utility of a drug are based on improved pharmacodynamic specificity (if the mechanisms of toxic and therapeutic effects differ) or an enhanced pharmacokinetic selectivity (distribution to the desired target site). Molecular selectivity of drugs binding to specific receptors helps in the development of new therapeutic agents displaying fewer side effects. ○ Raclopride is a highly selective antagonist of dopamine D2 and D3 (but not D1, D4 or D5) receptors. It is a potent antipsychotic agent used in the treatment of schizophrenia ○ Use of raclopride leads to fewer of the troublesome side effects (e.g. antipsychotic induced Parkinsonism) that are seen when all dopamine receptor subtypes are blocked. ○ The use of specific antagonists also helps in understanding disease mechanisms. That D1 receptor specific antagonists have no utility in the treatment of schizophrenia tells us that dopamine actions at D1 receptors are not important in schizophrenia. Degrees of selectivity: An example of a drug with extremely high selectivity which binds only the Na+ channels, blocking action potential propagation. There are also much less selective drugs, -CH2-CH2-CH2-N-(CH3)2, which enables a compound (at least to some extent) to interact with receptors for histamine, acetylcholine and possibly catecholamines. If the R-group is large, it can also function as an antihistamine or a local anesthetic Chlorpromazine, procaine and diphenhydramine share a number of properties: ○ They are all good local anesthetics, H1 receptor antihistamines and myocardial antiarrhythmics. ○ However, unique parts of each of their molecules also give them pharmacological properties that are not shared with the other compounds. Pharmacokinetic selectivity: For those drugs that either do not act selectively on particular receptors, or act on receptors that are found on many cell types or tissues, selectivity can still be obtained due to: 1. Selective distribution of drug to an intended site  2. Metabolic differences that make one tissue more sensitive to the effect of the drug than another. Geriatric Pharmacology: Elderly constitute 12% of the population but consume 31% of prescribed drugs in US Elderly more sensitive to drugs and exhibit more variability in response (kidneys less effective, fat contents change) Altered pharmacokinetics Multiple and severe illnesses. multiple drug therapy and usage Poor compliance “Individualization of treatment is essential: each patient must be monitored for desired responses and adverse responses, and the regime must be adjusted accordingly” Are there non drug measures that can be incorporated into the patient's care to reduce the number of drugs prescribed? Increased incidence of chronic conditions are one ages: Diabetes, Hypertension, Heart Failure, Ischemic Heart, Disease, Asthma/COPD, Arthritis, Alzheimer’s Disease, Urinary problems Changes in geriatric patients: Increases in body fat (25-30%) - reduces plasma levels of lipid soluble drugs Increase in total body water by 25% - increases concentration of water soluble drugs and intensity of response; greater risk for dehydration Concentration of serum albumin- malnourishment decreases albumin and results in increased drug levels Metabolism: hepatic functions in elderly and drug levels increase (diazepam, theophylline) Stomach pH decreases; blood flow ; decrease in gut motility (slow onset) In the elderly, muscle decreases by 25%. Excretion: decline (40-50%) of renal function in elderly may lead to higher serum drug levels and longer drug half-life. Reduced renal clearance of active metabolites may enhance therapeutic effect or risk of toxicity (e.g. digoxin, lithium, aminoglycosides, vancomycin) Adverse drug reactions in geriatrics: Seven times more likely in elderly 16% of hospital admissions 50% of all medication-related deaths Drug accumulation secondary to reduced renal function Polypharmacy : dangerous practice (drug-drug interactions) Greater severity of illness Presence of multiple pathologies Increased individual variation Inadequate supervision of long-term therapy Poor patient compliance Reasons for non-compliance include complex drug regimens, intentional non-adherence, and dementia and cognitive impairment Solutions: Start with a low dose and titrate slowly: Simplify regimen (once or twice daily dosing) Consolidate medications  Use of blister packs, pill boxes, calendars, watches, other reminders Reduce costs (e.g., generics, pill splitting)