Introduction to Pharmacology Definitions x Drug: x Pharmacology: x Clinical Pharmacology: x Therapeutics: Properties of an ideal drug (most important) x Effectiveness: x Safety: x Selectivity: Additional Properties of an Ideal Drug x Reversible action x Predictability x Ease of administration x Freedom from drug interactions x Low cost x Chemical stability x Possession of a simple generic name Landmark Drug Legislation x Pure Food and Drug Act of 1906: Set standards for drug quality and purity. Required drugs to be free of adulterants x The Food, Drug and Cosmetic Act (1938): Regulated drug safety and development of Food and Drug Administration (FDA) x Harris-Kefauver Amendment (1962): This amendment increased the rigor for testing of new drugs for safety and required all drugs to proven to be effective. x Controlled Substance Act (1970): Established rules for manufacture and distribution of drugs having potential for abuse (Schedules I-V) Drug Names x Chemical name: Indicates the chemical make-up of the drug x Generic name: Derived from the chemical name x Brand Name – (Trade Name ®) refers to the originally manufactured, patented drug. FDA Pregnancy Categories Human studies show no fetal risk. A Animal studies show no fetal risk. B C Either animal studies do show fetal effects or no studies exist. Drug should only be given if the potential benefits justify the potential risk. Evidence of human fetal harm exists. D Contraindicated! Risk to fetus clearly outweighs any possible benefit. X Major revisions to this rating system have occurred: changed to three categories— fetal risk summary, clinical considerations, and data Understanding Your Drug Information Resources Parts of your Drug Information Resource x *Therapeutic Class (Pharmacological Class): A way to categorize the drug. Usually based on either its chemical structure, its mechanism of action, or generally just what it does. Examples: non-steroidal anti-inflammatory drug (NSAID), antihypertensive, opioid, tricyclic antidepressant, anti-epileptic, calcium channel blocker, ACE-inhibitor, beta-blocker. x *Mechanism of Action: How does it work? How does it do what it does? x *Indications (Therapeutic Use): What is it used for? What does it treat? Examples: prevent stroke, treat HTN, prevent osteoporosis, vitamin supplement, analgesic. x Usual Dose Different doses may be offered for different patients, uses, & routes of administration. For example: adults, children, elderly, different dosage forms, renal failure, liver failure, different therapeutic uses, special circumstances. The drug dose is generally provided as the strength (or volume if a liquid) followed by the frequency (how often it is taken each day). Examples: 20mg daily; 1 gram 3 times daily; 20 units SQ with breakfast. x Dosage Forms (How Supplied): Strength, tab, cap, liquid, sustained release, injection x *Contraindications / Precautions / Warnings Who should not use this product? Allergy precautions (known hypersensitivity reactions). Obviously if you know you are allergic to a drug you don’t use that drug. Examples: Avoid use in persons with renal failure or heart failure. Contraindicated in post hip fractures. Contraindicated in pregnancy. Use caution in persons with history of angina. x Adverse Reactions (Adverse effects) Describes expected incidence & rate of adverse effects; usually reported by body system Remember, not all known adverse effects are listed in quick reference drug books. It is usually important to be familiar with the most common adverse effects and the lifethreatening adverse effects. You should also pay attention to any adverse effects that might impact your patient’s physical therapy. x FDA Pregnancy Categories Categorized as A,B,C,D,& X. A&B: generally safe. C gray area. D some kind of problem with the drug exists. X contraindicated. Although drug books provide this information, this area requires an in depth understanding of the drug’s specific teratogenic risk. x Drug Interactions Describes how to avoid the interaction if possible or the type of interaction. Usually describes what “bad thing” will happen if the drugs are used together. x Onset of Action: How soon until drug takes effect. x Duration of Action: How long the drug will exhibit its effects. x Half-Life: Length of time to reduce blood levels by one half. x Monitoring Parameters Physical parameters (Example: heart rate, respiratory rate, temperature) Labs (Example: blood levels, liver & renal function tests, white blood cell counts) Pay special attention to things that may require monitoring during physical activity. x Administration Instructions Nursing administration instructions or patient administration instructions. Examples: Do not crush. Take with food. Take on an empty stomach. Take at bedtime. x Patient Instructions Always read this section!! Provides a brief synopsis of the most important things for the patient to know about the drug. Information often overlaps with other sections. Basic Concepts of Pharmacokinetics & Pharmacodynamics x x Pharmacokinetics - a quantitative approach to describe the behavior of a drug in the body. » What does the body do to the drug? Pharmacodynamics – impact of drugs in the body. » What does the drug do to the body? The Four Pharmacokinetic Phases (1) Absorption x x Absorption – movement of drug from its site of administration into the systemic circulation. Absorption is not always desired, as with inhaled or topical steroids or the antibiotic neomycin that is used topically in the GI tract. Commonly Used Routes of Administration Passage of Drugs across Membranes x Channels or pores: Only very small drugs may do so. x Transport system: Selective molecule carriers x Direct penetration: Drugs must be lipid soluble (lipophillic) to dissolve into the cell membrane. Most common method of drug movement across membranes. pH Dependent Ionization x Many drugs can exist in a charged or an uncharged form. x The percentage of drug that is present in the charged: uncharged form at a given time depends on the pH of the surrounding medium. x Acidic drugs tend to ionize in basic (alkaline) media. x Bases trend to ionize in acidic media. Bioavailability x Bioavailability - fraction (%) of drug available in bloodstream after administration as compared to the IV route. x IV route is 100% bioavailable. x IM & SC route is also usually 100% bioavailable, although absorption may be delayed. x The AUC (area under the curve) for each route is calculated & compared. Patient Variables that Affect Absorption x Infant skin is much more absorbent than adult. x Broken or rashy skin or hot/sweaty/moist skin is more absorbent. x Patients with bowel resections. x Diarrhea or Constipation - anything affecting GI motility might be expected to affect the extent & rate of absorption, especially sustained release (SR) products. x Stomach acidity x Presence or absence of food. Factors that Affect Absorption x Lipid solubility: A drug must be lipid soluble for adequate GI absorption. x Rate of Dissolution: liquid > chewable > tablet/capsule > enteric coated > sustained release x Surface area: larger surface area > faster absorption x Blood Flow: greater blood flow at the absorption site = faster rate of absorption Clinical Relevance of Bioavailability x Explains why the normal IV dose is the same as the normal oral dose for some drugs, but not other drugs. x Explains why some drugs are not effective if given by different routes. Some drugs are not effective given orally, or rectally, or topically. x Explains the importance of taking some drugs with food, but others on an empty stomach. (2) Distribution x x x Distribution - movement of drug into the various body fluids & tissues. Volume of Distribution (Vd) - mathematical concept describing the amount of drug in the body in relation to the concentration of drug in the plasma. Vd is useful in estimating the loading dose necessary to achieve adequate plasma levels. Drug Distribution x Blood-Brain Barrier: only lipid soluble drugs can cross the BBB & reach the CNS x Placental Barrier: lipid soluble drugs can cross & reach the developing fetus x Breast milk: most drugs can enter a nursing mother’s milk supply x Fluid areas & Lipid tissues Protein Binding x Protein binding - some drugs are bound to plasma proteins, mostly albumin. Drugs bound to these proteins are pharmacologically inactive while bound. x The amount of drug bound at a given time is expressed as a percent. As the free drug is cleared, some of the bound drug will become unbound to maintain a constant percentage. The binding is therefore reversible & not permanent. Variables Affecting Vd & Distribution x The body composition of infants has a larger % of water & lesser % of muscle mass than adults do. x Obese patients may have a larger than expected volume of distribution (Vd) for drugs that are highly distributed into adipose tissue. x Significant changes in body weight or body composition can alter Vd. x Malnourished patients may have less serum proteins (i.e. albumin) available for drug binding. x Neonates and elderly have more permeable blood brain barriers. (3) Metabolism x x x x x x Metabolism – biotransformation - chemical alteration of the parent compound usually resulting in enhanced excretion, inactivation, or sometimes active metabolites. Enzymatic process. Usually occurs in the liver. First-pass metabolism – drugs absorbed in the small intestine are first exposed to the liver and may be extensively metabolized before reaching systemic circulation. » 1st-pass metabolism can greatly lower % bioavailability Prodrug – inactive compound that must be metabolized in order to become active. Phase 1 Reactions – Hepatic microsomal enzyme system: Cytochrome p450 (CYP2D6, CYP3A3/4, etc) Phase 2 Reactions – Usually no change with age (4) Excretion x Excretion – process by which the drug is eliminated from the body. Some drugs are excreted after metabolism. Some drugs are excreted “unchanged”. » Kidney, Bile, Intestine, Lung, Saliva, Skin Drug Clearance x Clearance – a general term used to describe the volume of blood which is completely cleared of a drug per unit of time. x Clearance includes the combination of metabolism or excretion by any route. Half-life (t 1/2) x Half-life (t1/2) – time required for the drug’s plasma concentration to be reduced by one-half. x Takes 4 – 5 half-lives for a drug to be considered “cleared”. x Most drugs follow “linear kinetics.” That is, the half-life is concentration & dose independent. » t 1/2 does NOT depend on dose Variables that Affect Clearance (Metabolism / Excretion) x Neonates have immature / underdeveloped metabolic pathways & renal function. x x Infants & children have high liver metabolism and excretion rates. There is a natural decline in some liver enzyme activity and in renal excretion with age. x x Hepatitis or alcohol abuse may reduce liver metabolism. Interacting medications may affect metabolism. x x Genetics can play an important role in metabolism (Examples: warfarin, codeine) Renal disease may reduce excretion of renally cleared medications. For patients receiving dialysis, adequate drug clearance may or may not be occurring. Congestive heart failure may reduce blood flow to the liver, kidney, and other organs that may cause a reduction in clearance. x Pharmacodynamics **Dose Response Relationship** – relationship between size of dose and intensity of response Therapeutic Window x Minimal Effective Concentration: Levels lower than the minimum effective concentration will not be effective. x Toxic Concentration: Levels near this dose may cause dramatic, unusual adverse effects, even death. x Therapeutic Index – ‘therapeutic window’ is a measure of the drug’s safety. It is the relationship between beneficial & adverse effects of a medication. Onset of Action: The amount of time it takes to reach the minimum effective concentration Half-life vs. Duration of Effect x Duration of Action – length of time a drug can be expected to exhibit its pharmacological effect. x Half-life specifically refers to plasma concentrations only, while duration of effect refers to the pharmacological action. x Duration of Action usually correlates with the half-life of the drug, but not always. Potency vs. Efficacy x Efficacy – the ability of a drug to produce a desired therapeutic effect. x Potency – measure of the amount of drug (dose,mg) required to produce a given degree of effect. x Potency vs. Efficacy – potency is rarely of clinical importance. Example: Pepcid 20mg will produce the same clinical effect as Zantac 150mg. Thus, Pepcid is more potent than Zantac, but both drugs are equally effective. **Mechanism of Action** x x x x x Receptors Receptor Theory – a drug produces an effect by combining with some specific molecular constituent (receptor). The function of the receptor or cell is modified to produce a measurable effect. Agonist – a drug that mimics some natural compound by binding with the receptor & stimulating some cellular response. Antagonist – a drug that binds with a receptor, blocks the receptor from stimulation, and prevents it from being triggered normally. Affinity – measure of the strength of attraction between a drug and its receptor. Describes the tightness of the bond. A drug with a high affinity to a certain receptor is very likely to elicit that response. A drug with a low affinity, is less likely to elicit that response, or may only do so in some patients or when used in very high doses. Selectivity – refers to the degree to which a drug acts upon one site relative to all possible sites. Usually, the more selective a drug is, the fewer adverse effects it will cause. Adverse Drug Reactions x ADR – any undesired, unintended response to a drug. » Exaggerated drug response: i.e. a blood pressure medication that unexpectedly bottoms out the patient’s blood pressure. » Adverse effect: undesired pharmacological effects of a drug; usually dose related » Allergic or hypersensitivity reaction » Toxicity: harmful or destructive effects of a drug often seen when therapeutic doses are x exceeded, the drug is used for a longer period of time than is recommended, or the drug is not properly monitored. Many use the terms toxicity & adverse effect interchangeably. » Drug interaction that causes increased adverse effects or decreased efficacy Drugs are poisons with therapeutic adverse effects. Intolerances vs. Drug Allergies x Intolerance – adverse effect of a drug that limits its usefulness or acceptance in a patient. x Drug Allergy – immune system mediated response, non-dose related, unpredictable. » Rash, hives, itching » Anaphylactic reaction: bronchoconstriction, swelling of lips, face, throat, tongue, severe hypotension ADRs / Drug Interactions / Patient Specific Variables x High Risk Drugs are those with a narrow therapeutic index, high incidence of adverse effects, or high incidence of allergic reactions. x High Risk Patients are those that would be least likely to tolerate adverse effects or loss of efficacy; i.e. the very young, the elderly, brittle diabetics, patients predisposed to arrhythmias, or epilepsy. Interpatient Variability in Drug Responses x Allergy history x Age x Weight – body size x Disease states x Genetics x Polypharmacy x Compliance Drug Interactions Drug-Drug Interaction – modification of the effects of one drug by the prior or concomitant administration of another. The four mechanism of drug interactions are 1) direct chemical interactions, 2) pharmacokinetic interactions, 3) pharmacodynamic interactions, & 4) combined toxicity Four mechanisms 1) Direct Chemical Interaction (precipitation, inactivation) 2) Pharmacokinetic Interactions a) Altered GI Absorption (altered pH, altered intestinal flora, chelation, mucosal damage) Altered pH x Non-ionized form of drug is more lipid soluble & easily absorbed – Example: ketoconazole/antacids (ketoconazole requires acidic environment for absorption) Chelation (Chemical bonding that prevents absorption) Example: ciprofloxacin / polyvalent cations (Mg++, Fe+++) Example: cholestyramine / digoxin or thyroid b) Altered Distribution Protein Displacement x Drugs bound to plasma proteins are pharmacologically inactive & exist in equilibrium between bound & unbound forms. x Any drug which is also protein bound may upset this equilibrium when added to or deleted from a patient’s drug regimen. x Usually only clinically significant for highly bound drugs (> 90%) Example: Bactrim / warfarin (Warfarin is displaced from albumin which causes a transient increased level of anticoagulation. c) Altered Metabolism (enzyme induction & enzyme inhibition) x Concurrent administration of two drugs metabolized by the same liver enzyme system can cause increases or decreases in blood levels of one or both agents. x Most of these interactions involve the cytochrome p450 system, which has multiple enzyme subsets. Enzyme Induction x n Metabolism = lower drug levels = loss of efficacy x Caused by one drug inducing (speeding up) the shared metabolic pathway Examples of inducers: carbamazepine, phenytoin, phenobarbital, chronic alcohol, cigarette smoking (May take 7-10 days before the interaction is seen) Enzyme Inhibition (most common type of DI) x ↓ Metabolism = higher levels = increased effects, adverse effects, & toxicity x Caused by competition for the same metabolic pathway Examples: cisapride, metronidazole, erythromycin, ketoconazole, cimetidine d) Altered renal excretion x Decreased cardiac output o decreased renal blood flow o decreased drug filtration o decreased drug excretion 3) Pharmacodynamic Interactions (Synergistic / Antagonistic Drug Interactions) a) Synergistic Effects: Occurs when the effects of two drugs are greater than would have been predicted from each of their effects alone. x 1+1=3 Example: two different blood pressure medications may dramatically lower pressure Example: morphine + diazepam (Valium) may cause life-threatening respiratory depression b) Antagonistic Effects: Occurs when the effects of two drugs are less than predicted from their effects when given alone. x 1+1=0 Example: a diuretic will reduce fluid retention while an NSAID may increase fluid retention Example: hydrochlorothiazide + spironolactone may balance blood potassium Example: vitamin K counteracts warfarin 4) Combined toxicity Example: isoniazid and rifampin both cause hepatic injury Strategies to Prevent DIs x Perform a complete medication history including Rx, OTC, & herbal drugs. x Be familiar with the most common drug interactions & adverse effects of your patients’ medications; and look it up if you do not know. x Avoid use of unnecessary drugs. x Select a non-interacting medication. x Separate chelating or pH interacting drugs (antacids) by at least 2 hours. x Monitor more closely when adding or deleting possible interacting medications. Plasma levels Efficacy, adverse effects, or toxicity Drug-Food Interactions x The absorption of some drugs will be enhanced if taken with food. x The absorption of other drugs may be hindered if taken with food & should be taken on an empty stomach. Empty stomach is defined as at least 1 hr before food or 2 hrs after food. x Grapefruit Juice: can cause significant cytochrome p450 interactions x Caffeine can increase theophylline toxicity. Broccoli & Brussels sprouts can decrease efficacy of warfarin. Alcohol increased Tylenol toxicity. Adverse Drug Reactions (ADR) x Mild—drowsiness, nausea x Severe—depression, anaphylaxis, hemorrhage x Most common in elderly and very young x Identify and report ADR’s Medication errors x Causes: wrong patient, wrong drug, wrong route, wrong dose x Ways to reduce errors include Computerized Physician Order Entry (CPOE), including Pharmacists on rounds, bar code technology x Serious medications errors should be reported Keep in Mind x Every drug with a pharmacological action has the potential for adverse drug reactions and/or drug interactions. x Expect the incidence of adverse effects & drug interactions reported with any new drug to increase after that drug is brought to market. x It is impossible to predict what the effect of multiple combinations of medications will have on a patient. Drug Therapy Considerations x The object of the game: Provide the maximum benefit with the minimum harm. x Is drug therapy necessary at all? x Examine interpatient variables? x How effective is the drug? Risk / Benefit? x Can / will the patient be compliant? Can the patient afford it? Does the patient understand? x What is the endpoint of therapy?