I.

Unit 1 Introduction to Pharmacology Orientation to Pharmacology (Chapter 1) A. Four Basic Terms 1. Drug any chemical that can affect living processes 2. Pharmacology the study of drugs and their interactions with living systems 3. Clinical Pharmacology the study of drugs in humans 4. Therapeutics/Pharmacotherapeutics the use of drugs to diagnose, prevent, or treat disease or to prevent pregnancy (ie, the medical use of drugs) B. Properties of an Ideal Drug 1. The Big Three i. Effectiveness an effective drug is one that elicits the responses for which it is given ii. Safety a safe drug is one that cannot produce harmful effects even if administered in very high doses and for a very long time iii. Selectivity a selective drug is one that elicits only the response for which it is given and would not produce side effects 2. Additional Properties of an Ideal Drug i. Reversible Action it is important that effects be reversible or that they subside within an appropriate amount of time ii. Predictability it is helpful if we know how a patient will respond to a drug before it is administered iii. Ease of Administration the route of administration should be convenient and the number of doses per day should be low iv. Freedom from Drug Interactions ideally would not interact with other agents v. Low Cost easy for the patient to afford vi. Chemical Stability able to retain activity indefinitely (ie, shelf stable) and not lose effectiveness in solution vii. Possession of a Simple Generic Name easy to recall and pronounce 3. Because No Drug is Ideal. i. All members of the healthcare team must exercise care to promote therapeutic effects and minimize drug-induced harm C. The Therapeutic Objective to provide maximum benefit with minimum harm D. Factors That Determine the Intensity of Drug Responses 1. Administration i. Dosage size and the route and timing of administration are important determinants of drug responses a. The intensity of the response is determined by the concentration of the drug at its sites of action b. The primary determinant of this concentration is the administered dose ii. Incorrectly administered drugs may result in toxicity or treatment failure 2. Pharmacokinetics the impact of the body on drugs (four major processes) i. Absorption movement from the site of administration to the blood ii. Distribution movement from the blood to tissue to cells iii. Metabolism alteration of drug structure by enzymes iv. Excretion movement of drugs out of the body 3. Pharmacodynamics the impact of drugs on the body i. Determine the nature and intensity of the drug response ii. The initial step is binding of the drug to its receptor, followed by a sequence of events that results in a response iii. The patients functional state can influence this process 4. Sources of Individual Variation i. Drug interactions ii. Physiological variables (age, gender, weight, etc) iii. Pathological variables (especially diminished function of the kidneys and liver) iv. Genetic variables

II.

Pharmacokinetics (Chapter 4) A. Passage of Drugs Across Membranes 1. Membrane Structure i. Recall: cellular membranes are composed of a phospholipid bilayer that is hydrophobic on each surface and hydrophilic in the center with proteins/carbohydrates attached to the surface and embedded in the membrane ii. Cells composing biologic membranes are packed too tightly for drugs to pass between them iii. Drugs cannot cross membranes unless they can pass through single cells 2. Three Ways to Cross a Cell Membrane i. Channels and Pores a. Very few drugs cross membranes this way because channels/pores are very small b. Small ions, like K and Na, are able to cross membranes using channels/pores ii. Transport Systems carriers that move drugs from one side of the cell to the other a. Some require energy, others do not 1.) Facilitated diffusion uses a carrier protein, but follows the concentration gradient and requires no energy input 2.) Active transport uses a carrier protein and pumps against the concentration gradient, requiring ATP b. All transport systems are selective c. P-Glycoprotein the multidrug transporter protein 1.) Transmembrane protein that transports drugs out of cells 2.) Found in the liver, kidneys, placenta, intestine, and capillaries of the brain iii. Direct Penetration of the Membrane a. Most drugs are too large to pass through channels/pores and lack any transport system so they rely on direct penetration of membranes b. In order to penetrate the membrane, the drug must be lipid soluble c. Polar molecules and ions are not lipid soluble and cannot penetrate membranes 3. Polar Molecules uneven distribution of electrical charge but not net charge (ie, H2O) 4. Ions molecules with a net positive or negative charge that cannot penetrate membranes unless very small i. Quaternary Ammonium Compounds molecules that contain at least one atom of N and carry a positive charge at all times ii. pH-Dependent Ionization a. Many drugs are weak organic acids or weak organic bases b. Whether or not an organic acid/base carries a charge is determined by the pH of the surrounding medium 1.) Recall: Acids are proton donors (ie, they give up H+ ions) and become negatively charged when ionized 2.) Bases are proton acceptors (ie, they take up H+ ions) and become positively charged when ionized c. Acids tend to ionize in alkaline environments d. Bases tend to ionize in acidic environments e. Thus, drugs that are weak organic acids will remain deionized in the stomach (more acidic) and can cross the membrane to be absorbed into the blood, but will not be able to cross the intestinal wall. Drugs that are weak organic bases will ionize in the stomach and be unable to cross the membrane, but will deionize in the intestine (more alkaline) and be able to cross the membrane to be absorbed into the blood. iii. Ion Trapping (pH Partitioning) a. When the pH of a fluid on one side of a membrane differs from the pH of the other side, drug molecules tend to accumulate on the side that favors ionization 1.) Acidic drugs will accumulate on the alkaline side 2.) Basic drugs will accumulate on the acidic side b. This concept is important when treating a poisoning because manipulation of urinary pH can draw toxic substances from the blood into the urine for excretion

B. Absorption movement of a drug from its site of administration into the blood 1. Factors Affecting Drug Absorption i. Rate of Dissolution drugs in formulations that allow rapid dissolution have a faster onset ii. Surface Area the larger the surface area for absorption, the faster absorption will be (oral drugs are usually absorbed from the small intestine rather than the stomach because the microvilli lining has an extremely large surface area) iii. Blood Flow drugs are absorbed most rapidly from sites where blood flow is high a. Blood containing newly absorbed drug is rapidly replaced with drug-free blood, maintaining a large concentration gradient between the blood and the outside iv. Lipid solubility lipid-soluble drugs readily cross the membranes that separate them from the blood and so are more rapidly absorbed than non-lipid-soluble drugs v. pH Partitioning absorption is enhanced when the pH favors ionization within the plasma 2. Characteristics of Commonly Used Routes of Administration i. Intravenous a. Barriers to Absorption none because absorption is bypassed b. Absorption Pattern instantaneous and complete c. Advantages 1.) Rapid Onset very important in emergencies 2.) Control since the entire dose is administered directly into the blood, we have precise control over levels of drug in the blood 3.) Use of Large Fluid Volumes some medications are not very soluble in water and must be diluted in large fluid volumes in order to dissolve 4.) Use of Irritant Drugs some medications are very irritating to the tissue and have to be diluted in large fluid volumes to reduce the risk for injury d. Disadvantages 1.) High Cost, Difficulty, and Inconvenience IV sets and their set-up charges are expensive Starting an IV line requires special training Patients have reduced mobility because they are tethered to their IV line 2.) Irreversibility dangerous because medication cannot be retrieved if administered incorrectly IV medications should be administered slowly (at least 1 min) 3.) Fluid Overload especially risky for pts with HTN, CHF, or renal disease 4.) Infection from contaminated medication or an infected IV site 5.) Embolism IV needle can damage venous wall and form a clot Hyper- or hypotonic IV fluids can destroy RBCs and form a clot Undissolved medication can block small vessels (always check that the IV fluid is clear and has no particulates) ii. Intramuscular a. Barriers to Absorption the capillary wall; large pores in capillaries facilitate rapid absorption b. Absorption Pattern 1.) Rapid with water-soluble drugs and slower with poorly soluble drugs 2.) Determined by Drug solubility in water Blood flow to the site of injection c. Advantages 1.) Can be used for parenteral administration of poorly soluble medications that cannot be given by IV 2.) Can be used for depot preparations (absorbed slowly over extended time) d. Disadvantages discomfort at injection site and inconvenient to administer iii. Subcutaneous all characteristics pretty much the same as IM administration

iv. Oral a. Barriers to Absorption 1.) Epithelial lining of GI tract Drug must pass through epithelial cells Absorption may be reduced by the action of P-glycoprotein 2.) Capillary wall (minor barrier) b. Absorption Pattern slow and highly variable, determined by: 1.) Solubility and stability of the drug 2.) Gastric and intestinal pH 3.) Gastric emptying time 4.) Food in the gut 5.) Coadministration of other drugs 6.) Special coatings on the drug preparation c. Drug Movement Following Absorption 1.) Drugs absorbed from all sites along the GI tract (except oral mucosa and distal segment of rectum) must pass through the liver before entering general circulation 2.) Some drugs undergo significant hepatic metabolism, others dont 3.) Some drugs enter enterohepatic recirculation and cycle from the liver, into the bile, and back into the small intestine d. Advantages 1.) Easy 2.) Convenient 3.) Inexpensive 4.) Ideal for self-medication 5.) Potentially reversible and thus safer than parenteral routes e. Disadvantages 1.) Variability difficult to control the concentration of drug at site of action, as well as onset, intensity, and duration of response 2.) Inactivation Some drugs are destroyed by the gastric pH Some drugs are destroyed by intestinal digestive enzymes Some drugs are inactivated as they pass through the liver 3.) Patient Requirements patient must be conscious and cooperative 4.) Local Irritation can cause GI discomfort (ie, nausea, vomiting, etc) v. Comparing Oral Administration with Parenteral Administration a. Oral medications are generally preferred because of ease, convenience, and relative safety b. Parenteral medications are preferred: 1.) In emergencies (rapid onset) 2.) When plasma drugs levels must be tightly controlled 3.) When drug is destroyed by pH or enzymes (ie, insulin) 4.) When PO treatment causes severe local injury (ie, chemotherapy) 5.) When treating a systemic disorder with a drug that cannot cross membranes 6.) When the prolonged effects of depot preps are needed 7.) When treating pts who cannot take PO meds 3. Pharmaceutical Preparations for Oral Administration i. Tablets a. Mixture of drug plus binders pressed together b. Tablets by different manufacturers have different rates of dissolution ii. Enteric-Coated Preparations a. Drugs covered in material (ie, fatty acids, waxes, and shellac) designed to dissolve in intestine but not stomach

b. Protects drugs from gastric pH and prevents gastric discomfort from drug c. Absorption is even more variable because of variation in gastric emptying time d. Sometimes enteric coatings fail to dissolve at all and no medication is absorbed iii. Sustained-Release Preparations a. Capsules filled with tiny spheres that contain actual drug b. Spheres have coatings that dissolve at variable rates so that drug is released steadily throughout the day c. This permits a reduction in the number of daily doses and steady drug levels d. High cost and potential for variable absorption 4. Additional Routes of Administration i. Topical ii. Transdermal iii. Inhaled iv. Rectal suppositories v. Vaginal suppositories vi. Direct injection into a specific site (ie, heart, joints, nerves, CNS) C. Distribution the movement of drugs throughout the body 1. Blood Flow to Tissues the rate drugs are delivered to a site depends on the blood flow to that site i. Abscess pus-filled pocket of infection that has no internal blood vessels so antibiotics cannot reach the bacteria within ii. Solid tumors high blood supply around the edges but very limited blood supply toward the core, resistant to drug therapy 2. Exiting the Vascular System i. Typical Capillary Beds most drugs pass between (leaky) capillary epithelial cells rather than through them ii. The Blood-Brain Barrier capillaries in the CNS have tight junctions that prevent leaking so drugs must be lipid soluble or have a transport system to pass through epithelial cells a. P-glycoprotein pumps drugs back into the blood and limits access to the brain b. This protects the brain from potentially toxic substances c. Not fully developed at birth so infants are especially vulnerable to CNS poisons iii. Placental Drug Transfer membranes of the placenta do not constitute an absolute barrier to the passage of drugs so extreme care must be taken when administering meds during pregnancy to protect the fetus from birth defects iv. Protein Binding a. Drugs form reversible bonds with various proteins in the body (especially plasma albumin) b. Drugs in the circulation exist either bound or unbound (free) c. Protein binding restricts drug distribution d. Drugs bound to albumin (or other proteins) cannot reach their sites of action, metabolism, or excretion e. Protein binding can be a source of drug interaction f. Competition for binding sites can increase the intensity of drug responses and cause toxicity 3. Entering Cells i. Some drugs enter cells to reach their sites of action ii. Almost all drugs enter cells for metabolism and excretion iii. Many drugs produce their effects by binding receptors on the cell surface D. Metabolism the enzymatic alteration of drug structure (occurs primarily in the liver) 1. Hepatic Drug-Metabolizing Enzymes i. The hepatic microsomal enzyme system (aka, the P450 system) performs most drug metabolism ii. Drug metabolism doesnt always result in the breakdown of drugs into smaller molecules iii. Drug metabolism can result in the synthesis of a molecule that is larger than the parent drug

2. Therapeutic Consequences of Drug Metabolism i. Accelerated Renal Drug Excretion a. The kidneys cannot excrete lipid soluble drugs b. Drug metabolism can convert lipid soluble drugs into more polar compounds to promote renal excretion ii. Drug Inactivation conversion of drug from active to inactive form iii. Increased Therapeutic Action conversion of drug from less active to more active form iv. Activation of Prodrugs conversion of drug from inactive (prodrug) to active form v. Increased or Decreased Toxicity from conversion to active or inactive form of drug 3. Special Considerations in Drug Metabolism i. Age drug-metabolizing capacity of infants is limited due to immature liver ii. Induction of Drug-Metabolizing Enzymes some drugs act on the liver to increase rates of drug metabolism (example: phenobarbital) a. A drug can increase its own rate of metabolism, requiring increased dosage b. Induction can accelerate the metabolism of coadministered drugs, requiring increased dosage iii. First-Pass Effect the rapid hepatic inactivation of certain oral drugs a. Oral drugs are absorbed along the GI tract and are carried directly to the liver via the hepatic portal vein b. Some drugs are completely inactivated in this first pass through the liver and must be administered parenterally to temporarily bypass the liver c. Example: nitroglycerin is administered sublingually to avoid the first-pass effect iv. Nutritional Status malnourishment may cause deficiencies in enzymatic cofactors v. Competition Between Drugs drugs metabolized by the same pathway may compete if administered together causing drug accumulation and possibly toxicity E. Excretion the removal of drugs from the body 1. Renal Drug Excretion i. Steps in Renal Drug Excretion a. Glomerular Filtration 1.) Small molecules are filtered through capillary pores into the urine 2.) Drugs bound to albumin remain in the blood b. Passive Tubular Reabsorption 1.) Afferent renal arteries (low drug concentration) run along the tubules (high drug concentration) creating a strong concentration gradient 2.) Lipid soluble drugs undergo passive reabsorption from the tubule back into the blood 3.) Ions and polar substances remain in the urine to be excreted c. Active Tubular Secretion 1.) Active transport systems (one for organic acids and one for organic bases) pump drugs from the blood into the urine 2.) P-glycoprotein also pumps drugs into the urine ii. Factors That Modify Renal Drug Excretion a. pH-Dependent Ionization manipulation of urinary pH can promote ionization of drugs and decrease passive reabsorption back into the blood (promotes excretion) b. Competition for Active Tubular Transport drugs that use the same transport systems compete for transport into the urine and delay renal excretion (this can be exploited to prolong the effects of a drug, if desired) c. Age newborns have immature kidneys and thus a limited capacity for excretion 2. Nonrenal Routes of Drug Excretion i. Breast Milk nursing mothers are advised to avoid all drugs to protect infants ii. Bile drugs taken up by the liver can be excreted into bile (enterohepatic recirculation) iii. Lungs especially important for excretion of volatile anesthetics iv. Sweat v. Saliva

III.

F. Time Course of Drug Responses 1. Plasma Drug Levels indicates the time course of drug action i. Clinical Significance of Plasma Drug Levels used to regulate drug responses b/c there is a direct correlation between therapeutic/toxic responses and the amount of drug in plasma ii. Two Plasma Drug Levels Defined a. Minimum Effective Concentration the plasma drug level below which therapeutic effects will not occur b. Toxic Concentration the plasma level at which toxic effects begin iii. Therapeutic Range range of plasma levels between the MEC and the toxic concentration a. The objective of drug dosing is to maintain plasma drug levels within the therapeutic range b. The width of the therapeutic range determines how easily a drug can be safely used 1.) Drugs with a wide therapeutic range can be safely administered with ease 2.) Drugs with a narrow therapeutic range must be closely monitored 2. Single-Dose Time Course i. Plasma drug levels rise during absorption and decline during excretion ii. Period of latency between drug administration and onset of effects iii. Rates of metabolism and excretion determine how long drug effects will last 3. Drug Half-Life the time required for the amount of drug in the body to decrease by 50% i. Drugs with short half-lives leave the body quickly ii. Drugs with long half-lives leave the body more slowly iii. Half-life determines the dosing interval 4. Drug Levels Produced with Repeated Doses multiple dosing leads to drug accumulation i. The Process by Which Plateau Drug Levels Are Achieved a. Repeated doses cause a drug to accumulate until a plateau is reached b. When the amount of drug eliminated between doses equals the dose administered, average drug levels remain constant and plateau has been reached ii. Time to Plateau approximately four half-lives iii. Techniques for Reducing Fluctuations in Drug Levels a. Administer drugs by continuous infusion b. Administer a depot preparation which releases the drug slowly and steadily c. Reduce the size of each dose and the dosing interval (keep daily dose constant) iv. Loading Doses vs. Maintenance Doses a. Loading dose (large initial dose) establishes high plasma drug level equivalent to plateau level for a smaller dose b. This reduces the time to plateau (useful for drugs with long half-lives) v. Decline from Plateau 94% of the drug will be eliminated from the body in four half-lives Pharmacodynamics (Chapter 5) A. Dose-Response Relationships determine the minimum amount of drug we can use, the maximum response a drug can elicit, and how much to increase the dosage in order to produce the desired response 1. Basic Features of the Dose-Response Relationship i. As the dosage increases, the response increases ii. Three phases a. Phase 1 curve is flat because dose is too low to elicit significant response b. Phase 2 increasing dose elicits a corresponding increase in response c. Phase 3 curve is flat again because the maximum response has been reached 2. Maximal Efficacy and Relative Potency i. Maximal Efficacy the largest effect that a drug can produce ii. Relative Potency the amount of a drug we must give to elicit an effect a. Rarely an important characteristic of a drug unless the potency is so low that the dose is inconveniently large b. The difference between pain relief with morphine vs. merpidine is like the difference between a dime and two nickels c. The potency is not related to the maximal efficacy

B. Drug-Receptor Interactions 1. Introduction to Drug Receptors i. Receptors are any functional macromolecules in a cell to which a drug binds to produce its effects ii. Receptors are generally the bodys own receptors for hormones, neurotransmitters, and other regulatory molecules a. Enzymes and ribosomes are considered target molecules, not true receptors iii. Receptor binding is usually reversible iv. Drug receptors are normal points of control of physiological processes v. Normally, receptors function is regulated by molecules supplied by the body vi. Drugs can only mimic or block the action of the bodys own regulatory molecules vii. Drugs can only alter the rate of normal physiologic processes and cannot make the body do anything it is not already capable of doing (except in gene therapy) 2. The Four Primary Receptor Families i. Cell Membrane-Embedded Enzymes a. Receptor spans the cell membrane b. Ligand-binding domain Is on the cell surface and catalytic site is on cell interior c. Binding of an agonist drug activates the enzyme d. Responses occur in seconds ii. Ligand-Gated Ion Channels a. Receptor spans the cell membrane b. Function to regulate the flow of specific ions into and out of the cell c. Binding of an agonist drug opens the channel, allowing ions to flow down the concentration gradient d. Responses occur in milliseconds iii. G Protein-Coupled Receptor Systems a. Three components 1.) Actual receptor 2.) G protein 3.) Effector (ion channel or enzyme) b. Binding of agonist drug activates the receptor which activates G protein which activates the effector Responses develop rapidly iv. Transcription Factors a. Found within the cell rather than on the surface b. Responses to activation of these receptors are delayed (hours or days) c. Transcription factors regulate gene expression (and thus, protein synthesis) d. Can only be activated by ligands that are sufficiently lipid soluble to cross the cell membrane 3. Receptors and Selectivity of Drug Action i. Drugs are selective because they act through specific receptors ii. Selective drug action is possible by the existence of many types of receptors, each regulating just a few processes iii. If a drug interacts with only one receptor that controls very few processes, then the effect of the drug will be limited iv. If a drug interacts with several receptors that each control several processes, then the drug will elicit a variety of responses v. Selectivity does not guarantee safety 4. Theories of Drug-Receptor Interaction i. Simple Occupancy Theory a. The intensity of drug response is proportional to the number of receptors occupied by the drug b. A maximal response will occur when all available receptors have been occupied c. Does not explain differences in potency or maximal efficacy

ii. Modified Occupancy Theory a. Affinity the strength of the attraction between a drug and its receptor 1.) Drugs with high receptor affinity are strongly attracted and vice versa 2.) Affinity of a drug for its receptors is reflected in its potency 3.) High affinity = high potency = effective in low doses b. Intrinsic Activity the ability of a drug to activate the receptor following binding 1.) Drugs with high intrinsic activity cause intense receptor activation 2.) Intrinsic activity of a drug is reflected in its maximal efficacy 3.) High intrinsic activity = high maximal efficacy = intense response c. The intensity of the response is still related to the number of receptors occupied 5. Agonists, Antagonists, and Partial Agonists i. Agonists molecules that activate receptors a. Drugs bind receptors and mimic the action of the bodys regulatory molecules b. High affinity and high intrinsic activity c. Do not necessarily make physiological processes go faster (depends on the action of the activated receptor) ii. Antagonists molecules that prevent receptor activation by endogenous regulatory molecules and drugs a. High affinity and no intrinsic activity b. Produce pharmacologic effects by down-regulating physiologic processes c. Response to an antagonist depends on how much agonist is present 1.) If there is no agonist, administering antagonist does nothing d. Noncompetitive (Insurmountable) Antagonists rarely used 1.) Bind irreversibly to receptor 2.) Reduces the totally number of receptors available for agonist activation 3.) Reduce the maximal response that an agonist can elicit 4.) Cannot be overcome, regardless of how much agonist is present 5.) Effects wear off as receptors are recycled by the cell e. Competitive (Surmountable) Antagonists 1.) Bind reversibly to receptor 2.) Compete with agonists for receptor binding 3.) Receptor will be bound by molecule with the highest concentration 4.) Can be overcome if sufficiently high amount of agonist is present iii. Partial Agonists agonist that has only moderate intrinsic activity a. The maximal effect is lower than that of a full agonist b. Can also function as an antagonist by competing with full agonists for binding 6. Regulation of Receptor Sensitivity i. In response to continuous activation/inhibition, the number of receptors on the cell surface can change, as can the sensitivity to agonist molecules ii. Constant stimulation by agonists causes the cell to be less responsive by destroying or modifying the receptor iii. Constant inhibition by antagonists causes the cell to be more responsive by synthesizing more receptors C. Drug Responses That Do Not Involve Receptors 1. Act through simple physical or chemical interactions with other small molecules 2. Antacids 3. Antiseptics 4. Saline laxatives 5. Chelating agents D. Interpatient Variability in Drug Responses it is impossible to predict exactly how an individual patient will respond to a drug 1. Measurement of Interpatient Variability requires analysis of research trials 2. The ED50 the dose that is required to produce a defined therapeutic response in 50% of the experimental population

3. Clinical Implications of Interpatient Variability i. The initial dose of a drug is necessarily an approximation and subsequent doses must be fine-tuned based on the patients response ii. When given an average effective dose (ED50), some patients will be undertreated and others will have received more drug than they need iii. Because drug responses are not completely predictable, you must look at the patient (and not the drug book) to determine if too much or too little medication has been administered iv. Because of variability in responses, nurses, patients, and other concerned individuals must evaluate actual responses and be prepared to inform the prescriber about these responses so that proper adjustments in dosage can be made E. The Therapeutic Index the ratio of a drugs average lethal dose (LD50) to its average effective dose (ED50) 1. Determines the drugs safety 2. LD50 the dose that is lethal to 50% of the laboratory animals tested 3. A relatively large therapeutic index indicates that a drug is relatively safe