Pharmacology Basic Principles Lecture Notes AY 2023-2024 PDF

PHARMACOLOGY BASIC PRINCIPLES Vince Edward C. Araneta, MD, FPAFP, CSPSH Objectives By the end of the unit, students will be expected to: 1. Define Pharmacology - its scope and its disciplines. 2. Explain the different pharmacokinetic processes such as absorption, distribution, excretion, biotran...

PHARMACOLOGY BASIC PRINCIPLES Vince Edward C. Araneta, MD, FPAFP, CSPSH Objectives By the end of the unit, students will be expected to: 1. Define Pharmacology - its scope and its disciplines. 2. Explain the different pharmacokinetic processes such as absorption, distribution, excretion, biotransformation, and to identify the different factors that affect these processes. 3. Identify and explain the different molecular models of receptors and how they work. 4. Differentiate an agonist from an antagonist.  What Loading… is Pharmacology? The body of knowledge concerned with the action of chemicals on biologic systems. References Basic Principles Loading… Part I  Pharmacology Medical Toxicology Pharmacology Medical Pharmacology: the area of pharmacology concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease, especially in humans. Toxicology: is the area of pharmacology concerned with the undesirable effects of chemicals on biologic systems.  The Nature of Drugs Composition: inorganic ions nonpeptide organic molecules small peptides and proteins nucleic acids lipids carbohydrates Source: plants or animals, but many are partially or completely synthetic  The Nature of Drugs Size & Molecular Weight Most weigh between 100 and 1000 Smaller than MW 100 rarely sufficiently selective in their actions Larger than MW 1000 often poorly absorbed & poorly distributed in the body  What is the difference between pharmacokinetics & pharmacodynamics?  Loading… Pharmacodynamics Pharmacodynamics  PHARMACODYNAMICS The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice. They may be briefly summarized as follows: 1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. 2. Receptors are responsible for selectivity of drug action. 3. Receptors mediate the actions of pharmacologic agonists and antagonists. High-Yield Terms Receptor A molecule to which a drug binds to bring about a change in function of the biologic system Inert binding A molecule to which a drug may bind without molecule or site changing any function Receptor site Specific region of the receptor molecule to which the drug binds Effector Component of a system that accomplishes the biologic effect after the receptor is activated by an agonist; often a channel or enzyme molecule, may be part of the receptor molecule Agonist A drug that activates its receptor upon binding High-Yield Terms Pharmacologic A drug that binds without activating its receptor antagonist and thereby prevents activation by an agonist Competitive A pharmacologic antagonist that can be overcome antagonist by increasing the concentration of agonist Irreversible A pharmacologic antagonist that cannot be antagonist overcome by increasing agonist concentration Physiologic A drug that counters the effects of another by antagonist binding to a different receptor and causing opposing effects Chemical antagonist A drug that counters the effects of another by binding the agonist drug (not the receptor) High-Yield Terms Allosteric agonist, A drug that binds to a receptor molecule without antagonist interfering with normal agonist binding but alters the response to the normal agonist Partial agonist A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist Graded dose-response A graph of increasing response to increasing drug curve concentration or dose Quantal dose-response A graph of the fraction of a population that shows a curve specified response at progressively increasing doses. The median effective (ED50), median toxic (TD50), and (in animals) median lethal (LD50) doses are derived from experiments carried out in this manner.  High-Yield Terms Efficacy, maximal The maximal effect that can be achieved with a efficacy particular drug, regardless of dose Potency The amount of drug needed to produce a given effect. Therapeutic Index Is the ratio of the TD50 (or LD50) to the ED50. V Safe drug : Represents an estimate of the safety of a drug. A ↑ toxic dose very safe drug might be expected to have a very ↓ effective dose large toxic dose and a much smaller effective dose. Therapeutic Window A more clinically useful index of safety. Describes minimum effective to the dosage range between the minimum effective min. toxic therapeutic concentration or dose, and the minimum toxic concentration or dose. Pharmacodynamic Principles: RECEPTORS Drug-receptor binding Activation of receptor AGONIST Drug-receptor binding Inhibition of receptor ANTAGONIST  RELATIONSHIP BETWEEN DRUG CONCENTRATION AND RESPONSE The relation between dose of a drug and the clinically observed response may be complex. In carefully controlled in vitro systems, however, the relation between concentration of a drug and its effect is often simple and can be described with mathematical precision. This idealized relation underlies the more complex relations between dose and effect that occur when drugs are given to patients. Concentration-Effect Curves & Receptor Binding of Agonists GRADED DOSE-RESPONSE RELATIONSHIPS When the response of a particular receptor-effector system is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration or dose is called a graded dose-response curve. GRADED DOSE-RESPONSE RELATIONSHIPS GRADED DOSE-BINDING RELATIONSHIP & BINDING AFFINITY It is possible to measure the percentage of receptors bound by a drug, and by plotting this percentage against the log of the concentration of the drug, a dose-binding graph similar to the dose- response curve is obtained. QUANTAL DOSE-RESPONSE RELATIONSHIPS When the minimum dose required to produce a specified response is determined in each member of a population, the quantal dose- response relationship is defined. When plotted as the percentage of the population that shows this response at each dose versus the log of the dose administered, a cumulative quantal dose-response curve, usually sigmoid in shape, is obtained. QUANTAL DOSE-RESPONSE RELATIONSHIPS EFFICACY Efficacy—often called maximal efficacy—is the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level. By definition, partial agonists have lower maximal efficacy than full agonists GRADED DOSE-BINDING RELATIONSHIP & BINDING AFFINITY POTENCY Potency denotes the amount of drug needed to produce a given effect. In graded dose-response measurements, the effect usually Loading… chosen is 50% of the maximal effect and the concentration or dose causing this effect is called the EC50 or ED50 (Figure 2–1A and B). QUANTAL DOSE-RESPONSE RELATIONSHIPS SPARE RECEPTORS Spare receptors are said to exist if the maximal drug response (Emax) is obtained at less than 100% occupation of the receptors (Bmax). In practice, the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd).  SPARE RECEPTORS AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS Modern concepts of drug-receptor interactions consider the receptor to have at least 2 states—active and inactive. In the absence of ligand, a receptor might be fully active or completely inactive; Many receptor systems exhibit some activity in the absence of ligand, suggesting that some fraction of the receptor is always in the activated state. Activity in the absence of ligand is called constitutive activity. AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS A full agonist is a drug capable of fully activating the effector system when it binds to the receptor. A partial agonist produces less than the full effect, even when it has saturated the receptors (Ra-Dpa +Ri-Dpa), presumably by combining with both receptor conformations, but favoring the active state. AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS In the presence of a full agonist, a partial agonist acts as an inhibitor. In this model, neutral antagonists bind with equal affinity to the Ri and Ra states, preventing binding by an agonist and preventing any deviation from the level of constitutive activity. In contrast, inverse agonists have a higher affinity for the inactive Ri state than for Ra and decrease or abolish any constitutive activity. ANTAGONISTS A. Competitive and Irreversible Pharmacologic Antagonists Competitive antagonists are drugs that bind to, or very close to the agonist receptor site in a reversible way without activating the effector system for that receptor A noncompetitive antagonist that acts at an allosteric site of the receptor may bind reversibly or irreversibly; a noncompetitive antagonist that acts at the receptor site binds irreversibly. ANTAGONISTS SIGNALING MECHANISMS Once an agonist drug has bound to its receptor, some effector mechanism is activated. The receptor-effector system may be an enzyme in the intracellular space (eg, cyclooxygenase, a target of nonsteroidal anti- inflammatory drugs) or in the membrane or extracellular space (eg, acetylcholinesterase). ANTAGONISTS B. Physiologic Antagonists A physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes. C. Chemical Antagonists interacts directly with the drug being antagonized to remove it or to prevent it from binding to its target THERAPEUTIC INDEX AND THERAPEUTIC WINDOW The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves. Represents an estimate of the safety of a drug. The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. SIGNALING MECHANISMS Once an agonist drug has bound to its receptor, some effector mechanism is activated. The receptor-effector system may be an enzyme in the intracellular space (eg, cyclooxygenase, a target of nonsteroidal anti- inflammatory drugs) or in the membrane or extracellular space (eg, acetylcholinesterase). SIGNALING MECHANISMS SIGNALING MECHANISMS RECEPTOR REGULATION Receptors are dynamically regulated in number, location, and interaction with other molecules. Changes can occur over short times (minutes) and longer periods (days). Frequent or continuous exposure to agonists often results in short term diminution of the receptor response, sometimes called tachyphylaxis. RECEPTOR REGULATION Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. The opposite change (upregulation) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation. Inert Binding Sites Drugs bind to these nonregulatory molecules in the body no discernible effect Albumin: an important plasma protein with significant drug- binding capacity Pharmacokinetics Pharmacokinetics High-Yield Terms Volume of distribution The ratio of the amount of drug in the body to the drug (apparent) concentration in the plasma or blood Half-life The time required for the amount of drug in the body or blood to fall by 50%. For drugs eliminated by first-order kinetics, this number is a constant regardless of the concentration Bioavailability The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation Peak and trough The maximum and minimum drug concentrations concentrations achieved during repeated dosing cycles High-Yield Terms Minimum effective The plasma drug concentration below which a patient’s concentration response is too small for clinical benefit (MEC) First-pass effect, The elimination of drug that occurs after administration presystemic but before it enters the systemic circulation (eg, during elimination passage through the gut wall, portal circulation, or liver for an orally administered drug) Steady state In pharmacokinetics, the condition in which the average total amount of drug in the body does not change over multiple dosing cycles (ie, the condition in which the rate of drug elimination equals the rate of administration) Effective Drug Concentration the concentration of a drug at the receptor site. If the rate of input is known, the remaining processes are well described by 2 primary parameters: apparent volume of distribution (Vd) and clearance (CL). These parameters are unique for a particular drug and a particular patient but have average values in large populations that can be used to predict drug concentrations. Volume of Distribution relates the amount of drug in the body to the plasma concentration according to the following equation: Volume of Distribution Volume of Distribution The Vd of drugs that are normally bound to plasma proteins such as albumin can be altered by liver disease (through reduced protein synthesis) and kidney disease (through urinary protein loss). On the other hand, if a drug is avidly bound in peripheral tissues, the drug’s concentration in plasma may drop to very low values even though the total amount in the body is large. Clearance Clearance (CL) relates the rate of elimination to the plasma concentration: For a drug eliminated with first-order kinetics, clearance is a constant; that is, the ratio of rate of elimination to plasma concentration is the same over a broad range of plasma concentration Clearance As in the case of Vd, clearance is sometimes expressed as CL per kg of body weight. Clearance depends on the drug, blood flow, and the condition of the organs of elimination in the patient. Clearance Half-Life Half-life (t1/2) is a derived parameter, completely determined by Vd and CL. Like clearance, half-life is a constant for drugs that follow first-order kinetics. Half-life can be determined graphically from a plot of the blood level versus time or from the following relationship: Half-Life  What is the half-life of drug X? A. 8 am: 100 mg B. 10 am: 75 mg C. 12 pm: 50 mg D. 2 pm: 25 mg Half-life: 4 hours Bioavailability The bioavailability of a drug is the fraction (F) of the administered dose that reaches the systemic circulation. Bioavailability is defined as unity (or 100%) in the case of intravenous administration. After administration by other routes, bioavailability is generally reduced by incomplete absorption (and in the intestine, expulsion of drug by intestinal transporters), first-pass metabolism, and any distribution into other tissues that occurs before the drug enters the systemic circulation. Bioavailability Extraction Removal of a drug by an organ can be specified as the extraction ratio, that is, the fraction or percentage of the drug removed from the perfusing blood during its passage through the organ. Drugs that have a high hepatic extraction ratio have a large first-pass effect and the bioavailability of these drugs after oral administration is low. Extraction Dosage Regimens A dosage regimen is a plan for drug administration over a period of time. An optimal dosage regimen results in the achievement of therapeutic levels of the drug in the blood without exceeding the minimum toxic concentration. To maintain the plasma concentration within a specified range over long periods of therapy, a schedule of maintenance doses is used. A. Maintenance Dosage Because the maintenance rate of drug administration is equal to the rate of elimination at steady state (this is the definition of steady state), the maintenance dosage is a function of clearance (from Equation 2). A. Maintenance Dosage The number of doses to be given per day is usually determined by the half-life of the drug and the difference between the minimum therapeutic and toxic concentrations (therapeutic window). If the difference between the toxic and therapeutic concentrations is small, then smaller and more frequent doses must be administered to prevent toxicity. B. Loading Dosage If the therapeutic concentration must be achieved rapidly and the Vd is large, a large loading dose may be needed at the onset of therapy. This can be calculated from the following equation: Therapeutic Window The therapeutic window is the safe range between the minimum therapeutic concentration and the minimum toxic concentration of a drug. These data are used to determine the acceptable range of plasma levels when designing a dosing regimen. Therapeutic Window Adjustment of Dosage When Elimination is Altered by Disease Renal disease or reduced cardiac output often reduces the clearance of drugs that depend on renal elimination. Alteration of clearance by liver disease is less common but may also occur. The most important renal variable in drug elimination is glomerular filtration rate (GFR), and creatinine clearance (CLcr) is a convenient approximation of GFR. Adjustment of Dosage When Elimination is Altered by Disease The dosage in a patient with renal impairment may be corrected by multiplying the average dosage for a normal person times the ratio of the patient’s altered creatinine clearance (CLcr) to normal creatinine clearance (approximately 100 mL/min, or 6 L/h in a young adult). Adjustment of Dosage When Elimination is Altered by Disease For example, if a drug is 50% cleared by the kidney and 50% by the liver and the normal dosage is 200 mg/d, the hepatic and renal elimination rates are each 100 mg/d. Therefore, the corrected dosage in a patient with a creatinine clearance of 20 mL/min will be: Adjustment of Dosage When Elimination is Altered by Disease Renal function is altered by many diseases and is often decreased in older patients. CLcr can be measured directly, but this requires careful measurement of both serum creatinine concentration and a timed total urine creatinine. Adjustment of Dosage When Elimination is Altered by Disease A common shortcut that requires only the serum (or plasma) creatinine measurement (Scr) is the use of an equation. One such equation in common use is the Cockcroft-Gault equation: The result is multiplied by 0.85 for females. Adjustment of Dosage When Elimination is Altered by Disease A similar equation for GFR is the MDRD equation: DRUG METABOLISM DRUG METABOLISM Many cells in tissues that act as portals for entry of external molecules into the body that expel unwanted molecules immediately after absorption. Biotransformation of drugs is one such process. It is an important mechanism by which the body terminates the action of many drugs. In some cases, it serves to activate prodrugs. TYPES OF METABOLIC REACTIONS Phase I Reactions - include oxidation, reduction, deamination, and hydrolysis Phase II Reactions - synthetic reactions that involve addition (conjugation) of subgroups to —OH, —NH2, and —SH functions on the drug molecule TYPES OF METABOLIC REACTIONS TYPES OF METABOLICLoading… REACTIONS SITES OF DRUG METABOLISM The most important organ for drug metabolism is the liver. The kidneys play an important role in the metabolism of some drugs. A few drugs (eg, esters) are metabolized in many tissues (eg, liver, blood, intestinal wall) because of the wide distribution of their enzymes. DETERMINANTS OF BIOTRANSFORMATIONS RATE The rate of biotransformation of a drug may vary markedly among different individuals. This variation is most often due to genetic or drug-induced differences. For a few drugs, age or disease-related differences in drug metabolism are significant. DETERMINANTS OF BIOTRANSFORMATIONS RATE Genetic Factors Effects of Other Drugs Enzyme Induction Enzyme Inhibition Inhibitors of Intestinal P-Glycoprotein DETERMINANTS OF BIOTRANSFORMATIONS RATE Genetic Factors Effects of Other Drugs Enzyme Induction Enzyme Inhibition Inhibitors of Intestinal P-Glycoprotein DETERMINANTS OF BIOTRANSFORMATIONS RATE DETERMINANTS OF BIOTRANSFORMATIONS RATE TOXIC METABOLISM Drug metabolism is not synonymous with drug inactivation. Some drugs are converted to active products by metabolism. If these products are toxic, severe injury may result under some circumstances. An important example is acetaminophen when taken in large overdoses. TOXIC METABOLISM