Introduction to Clinical Pharmacology for Physician Assistant Students PDF

Introduction to Clinical Pharmacology for Physician Assistant Students Jennifer Hofmann, PA-C, MS  Terminology in Pharmacology › Pharmacology - the study of how drugs interact with body constituents to produce therapeutic effects. › The effect of drugs on living systems › It is...

Introduction to Clinical Pharmacology for Physician Assistant Students Jennifer Hofmann, PA-C, MS  Terminology in Pharmacology › Pharmacology - the study of how drugs interact with body constituents to produce therapeutic effects. › The effect of drugs on living systems › It is a complex science that requires knowledge of biochemistry, physiology, organic chemistry and molecular biology.  Basics / Terminology and Definitions › Clinical Pharmacology- the effects of drugs on humans › Drug- any agent that affects living systems – anything that can be used to treat, diagnose or prevent disease. – 1) chemical name e.g. N-acetyl-p-aminophenol – 2) generic or trivial name (tells us nothing about the drug) acetaminophen – 3) abbreviation e.g. APAP – 3) brand name (created by manufacturer so you won't forget it) Tylenol® Basics / Terminology and Definitions Pharmacodynamics - biochemical & physiological effects of drugs and mechanisms of action – WHAT DRUG DOES TO BODY - HOW THEY WORK – Drug and receptor interactions INPUT › Pharmacokinetics - the time course of absorption, distribution, metabolism & excretion ABSORPTION, DISTRIBUTION, KIDNEY – ADME METABOLISM, EXCRETION – WHAT THE BODY DOES TO THE DRUG LIVER › Pharmacotherapeutics - prevention and treatment of disease – must consider benefit/risk ratio -good versus harm – Therapeutic: toxic effects  More Terminology › Toxicology - study of poisons (recognition, treatment, prevention) › a) Drugs- – side effects- at therapeutic doses – toxicity - at higher doses › b) Chemicals – not specifically used as therapy (household, industrial, environmental, abuse) › Teratology - the study of monsters - how drugs, taken during pregnancy, can effect the fetus morphologically – Drug labeling in pregnancy and reproduction (no longer categories A, B, C, D and X) – THE PREGNANCY AND LACTATION – LABELING RULE (PLLR) (next slides) › Pharmacogenetics/ pharmacogenomics   THE PREGNANCY AND LACTATION LABELING RULE (PLLR) › Four headings › Other headings: – Pregnancy Exposure Registry 1. Lactation information – Risk Summary* › – Risk Summary* – Clinical Considerations › – Clinical Considerations › Data – Data 2. Females and Males › Detailed description of the data that provide the scientific basis – of Reproductive Potential for the summary information presented in the Risk Summary › Include when there are requirements or and Clinical Considerations recommendations for pregnancy headings testing and/or contraception and/or when human and/or animal data suggest drug effects on fertility Pharmacogenetics and Pharmacogenomics Pharmacogenetics / pharmacogenomics Variability in Drug Response  Therapeutic Index (T.I.) › Therapeutic Index (T.I.)(margin of safety)- – In animals= LD50/ED50 – in humans the TI= TD50/ED50 = minimum toxic dose/minimum therapeutic dose. Dose response › a more dangerous drug has a lower therapeutic index curve › may require regular monitoring of drug levels › examples include: – warfarin – lithium – digoxin – phenytoin – a safer drug has a higher or wider therapeutic index AMOUNT › very large lethal dose, very small effective dose How does this relate to TI? Serum Drug Monitoring  Pharmacodynamics › For most drugs to work, they must arrive at their site of action in effective concentrations (relates to dosage or amount of drug) › This site of action is often a specific biological molecule, called a receptor. It may be a membrane or a membrane protein, or a cytoplasmic or extracellular enzyme. › The drug binding sites proteins, glycoproteins, or lipoproteins and have a three-dimensional structure or configuration. › The drug must bind with the receptor (binding site on receptor) , the receptor must be able to recognize the drug (specificity). – (Not every drug will combine with every receptor). This drug-receptor complex will produce a biological and measurable (observable effect)  Key: (A, C, substrates; B, D, products; R, receptor; G, G protein; E, effector [enzyme or ion Drug Receptor Interactions channel]; 5 types of Drug Receptor Interactions Drug Y, tyrosine; P, phosphate.) (review your physiology lectures) receptor interactions? What happens when drug binds to its receptor?  Pharmacodynamics- Terms › Agonist : – 1) is a drug that combines with a receptor and produces the same response as an endogenous chemical. – 2) is a drug that combines with a receptor and stimulates the release of an endogenous chemical. › Antagonist (blocker) – 1) is a drug the combines with a receptor used by an endogenous chemical and blocks or diminishes the response of the endogenous agent. – 2) is a drug that combines with a receptor and inhibits the release of an endogenous compound. www.youtub e.com/ watch? v=pHwmeh6 AzqU Pharmacodynamics: Agonists/ Antagonists › An agonist is said to have affinity for the receptor and efficacy (or intrinsic activity) effectiveness. › A partial agonist has affinity but low efficacy – Binds tightly but does not fully activate or turn on receptors › Competitive antagonism- agonist and antagonist compete for same receptor site – Agonist can overcome if high enough agonist concentration › Irreversible antagonist- covalent or tight bonds with D and R so R is unavailable and inaccessible to agonist › Non-competitive antagonism- agonist and antagonist bind at different sites on the same receptor and prevents activation of receptor › Assume there are 100 receptors at a site. › Fifty must be occupied for there to be an observable pharmacological response. Assume that one molecule of drug interacts with one receptor › if only 25 drug molecules are present to combine with receptors there is no observable response – as more molecules are introduced, there eventually will be an observable response (50-60). – as still more are is added we will see a pharmacological response (60-75) (therapeutic range) – ceiling effect (more drug will not change response saturation  More about AFFINITY and EFFICACY  Pharmacodynamics › Potency- Potency (strength) refers to the amount of drug (usually expressed in milligrams) needed to produce an effect, such as relief of pain or reduction of blood pressure. – drug A is said to be more potent than drug B. if the dose of A is less than B to achieve the same response. › Potency relates to affinity (“fit”) – (relates/ compares dosage of two or more drugs) › Example: Therapeutic goal: lower BP by 10 mmHg : – drug A does it at 5mg and Drug at 50 mg – Which is more potent? › Efficacy - is the magnitude of the maximum effect (predefined) intrinsic property /ability of drug – Example: regardless of dosage morphine is more effective than codeine comparing which is more potent and which drug is more effective better affinity more potency less you need  Dose – Response Curves Relationship between drug concentration and effects Dose (amount) vs Response (effect on body) Curve  More Terms in Pharmacodynamics › Tolerance reduced response to the same dose or increased dose needed for same response. – 1) change in receptor sensitivity (downregulation or diminished signaling effects after binding) – 2) change in pharmacokinetics of drug › Tachyphylaxis- while tolerance tends to occur slowly, tachyphylaxis happens quickly, after one or two doses. › Placebo Effect - psychological response -patient is given inert material and told it is a potent analgesic - as many as 35% of the population will respond.  Allergy (Hypersensitivity) › Allergy (Hypersensitivity) - an adverse immune reaction that results from a previous exposure to a particular chemical or one that is structurally similar. It is divided into 4 categories: – Type I - anaphylactic reaction, mediated by IgE antibodies. Reactions tend to occur quickly after challenge with sensitized allergen and is called an immediate hypersensitivity reaction. Symptoms include: urticaria, rash, vasodilation, hypotension, edema, inflammation, rhinitis, asthma, tachycardia, etc. They are the result of the release of histamine, prostaglandins and leukotrienes. – Type II - cytolytic reactions mediated by IgG and lgM antibodies that affect the cells of the circulatory system. They include hemolytic anemia, thrombocytopenia, granulocytopenia,systemic lupus erythematosus. These autoimmune reactions to drugs usually subside within several months after drug discontinuation. – Type III - Arthus reactions are mediated IgG where immune complexes are deposited in the vascular endothelium, where a destructive inflammatory response called serum sickness occurs. Symptoms include erythema multiforme, arthritis, nephritis, CNS abnormalities and myocarditis.(example: sulfonamide antibiotics) – Type IV - delayed hypersensitivity reactions are mediated by T-lymphocytes and macrophages. When sensitized cells come in contact with the antigen, lymphokines cause an inflammatory reaction. (example: poison ivy)  MORE Terms in Pharmacodynamics › Idiosyncrasy - an unusual response to a drug, usually caused by genetic differences in metabolism or immunologic mechanisms. › Hyperreactive- the intensity of a given dose of a drug is greater than anticipated. › Hyporeactive - the intensity of a given dose of a drug is less than anticipated. › There are times when a therapeutic effect is not observable. This is of particular concern when using drugs with a low therapeutic index or when underdosing a person can be as dangerous or lethal as overdosing. (example antibiotics). The alternative is to measure blood, serum or plasma levels of the drug. › In most cases there is a ratio between blood levels and tissue levels. › Peak and trough levels BREAK  PHARMACOKINETICS › PHARMACOKINETICS- what the body does to the drug over time › 4 phases – (Absorption, Distribution, Metabolism, Excretion) › To produce an effect a drug must be present in appropriate concentrations at its site of action. The body is a series of compartments separated by membranes › 1. What's a membrane? It is a lipid bilayer made up of phospholipids and cholesterol. to allow – The hydrophobic parts (tails) are in the middle and the hydrophilic ends are on the outside. Chemicals that are passive lipophilic (fat soluble) are attracted to the membrane, but not released. diffusion- – Large hydrophilic (water soluble) chemicals are repelled by the lipid segment of the membrane. Most drugs have small, non some degree of lipid and water solubility, so that they can be dissolved in an aqueous environment (plasma) and ionized, be transported across the membrane. lipophillic › Drugs with a higher lipid solubility cross membranes better than those with low lipid solubility. › Most drugs are weakly acidic or weakly basic, so that in some pH ranges they will be charged and in others uncharged. › The uncharged form of drug is lipid soluble and therefore crosses more readily Pharmacokinetic Principles: Passive Diffusion  Membranes and Drugs › How do drugs cross biological membranes? › Passive diffusion - proportional to concentration gradient. For non- electrolytes it is proportional to lipid solubility (partition coefficient). For electrolytes it is related to pH. – Most common – Small (