Pharmacology and Pharmacokinetics Module 4 PDF

MODULE 4  PHARMACOLOGY & PHARMACOKINETICS  TOXICOLOGY  INCOMPATIBILITIES & ADVERSE DRUG REACTION PHARMACOLOGY Pharmacology  Study of selective biologic activity of drugs  Study of substances that interact w/ living systems through chemical proces...

MODULE 4  PHARMACOLOGY & PHARMACOKINETICS  TOXICOLOGY  INCOMPATIBILITIES & ADVERSE DRUG REACTION PHARMACOLOGY Pharmacology  Study of selective biologic activity of drugs  Study of substances that interact w/ living systems through chemical processes, especially by binding to regulatory molecules & activating or inhibiting normal processes  Medical Pharmacology  is the area of pharmacology concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease, especially in humans. Drugs  Articles recognized in the official USP, official Homeopathic Pharmacopeia of the US or the official NF, or any supplements to any of them  Articles for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.  Articles, other than food intended to affect the structure or any function of the body of man or other animals  Articles intended for use as component of any articles specified in clause 1, 2, or 3: but does not include devices or their components parts or accessories.  Substances that act on biologic systems at the chemical (molecular) level and alter their functions(Katzung)  Drug receptors  The molecular components of the body with which drugs interact to bring about their effects  Nature of drugs  Drugs are chemicals that modify body functions. They may be ions, carbohydrates, lipids, or proteins. They vary in size from lithium (MW 7) to proteins (MW 50,000) Branches of Pharmacology Pharmacodynamics  is a branch of pharmacology that focuses on the study of biochemical & physiological effects of drugs & the mechanisms by which they produce such effects. ” what the drug does to the body”  deals with interaction of drugs w/ receptor  molecular consequences Biological effect  study of the biochemical & physiologic effects of drugs in biological systems Pharmacokinetics  is the quantitative measurement of drug absorption, distribution, and elimination (i.e., excretion and metabolism) and includes the rate processes for drug movement into the body, within the body, and out of the body. ”What the body does to the drug”  examines the moment of drug over time through the body Pharmacotherapeutics  Rational use of Dugs in the management of diseases Toxicology  branch that deals w/ the undesirable effects of chemicals on living systems, from individual cells to complex ecosystems Classification of Drugs:  Functional modifiers  Alters certain physiologic functions & activities of body cells  Examples:  Sensation of pain (analgesics, anesthetics)  Tachycardia (beta-blockers)  Morphine  narcotic analgesic; pain perception  Bevacizumab  for cancer; inhibit VRGF (vascular endothelial growth factor)  vascularization  Replenishers  Replaces/ replenish endogenous substance that are lacking/ deficient/ absent  Example:  DM type 1 (Insulin)  Pernicous Anemia (Vit B12) an autoimmune disease when immune system produces antibodies that target the parietal cells of the stomach that leads in inhibiting/ decrease HCL & Intrinsic Factor (which are important in VitB12 absorption having pernicious anemia can lead to Megaloblastic Anemia (cause neurologic effect) Vit B12  absorbed in terminal ileum; sources: meat products Causes of VitB12 deficiency: a. Chronic use of Proton pump Inhibitor b. H2 Blockers c. Diphylobotrium latum (fish tapeworm)  competes in Vit B12 absorption  Diarrhea (ORS)  Diagnostic Agents  Diagnosis or confirmation of diagnosis of certain diseases  Example:  Edrophonium (Tensilon®) Myasthenia gravis  Pulmonary challenge test; diagnosis of bronchial asthma (Histamine)  Radiopaque; to visualize the outline of the GIT (Barium sulfate)  Dobutamine  Schemia  Dobutamine/ Dipyridamole  used in pharmacologic stress testing  Tc99m stratum Thallium 201 Dx: Myocardial Ischemia  O2  cells are still viable Myocardial Infarction  no O2 supply  cells are dead (necrosis)  Chemotherapeutics Agents  Agents used to kill/ inhibit growth of cells considered as foreign to the body  Anti-infectives  Anti-microbials  Anti-neoplastics  Anti-cancer Principles of Pharmacodynamics: Mechanisms of Drug Action Classification of mechanisms based on the concepts of target proteins i. Non target protein-mediated a. Direct chemical interaction  Chelating agents o Dimercaprol for Pb, Ag, Hg, Ar o EDTA (emergency treatment for hypercalcemia, control of Ven arrhythmia due to digitalis o Calcium EDTA (Treatment of acute & chronic lead poisoning) o Defuroxamine (Desferal) for Fe toxicity  Neutralization reactions o Antacids Mg++ & Ca++ for HCl o Ammonium chloride o Sodium bicarbonate b. Colligative mechanism/mass effect  Lactulose  Mannitol (osmotic diuretic – renal tubule-early loop of henle) Creates a n osmotic gradient across renal tubule c. Counterfeit incorporation  Affects gene transcription  (purine & pyrimidine analogues; ex. Flucystosine, 5FU, & antimetabolites) ii. Target protein-mediated a. Structural proteins:  Tubulin, proteins present in microtubules (colchicines, vinca alkaloids)  Keratin (Griseofulvinincrease absorption w/ fatty food through pinocytosis) b. Regulatory 1) Transport Proteins (a) Voltage-gated Na channels  detect changes in environment  Inhibited by: Local Anesthetics, Class I Antiarrhythmic, Phenytoin, Carbamazepine (b) Voltage-gated Ca channels  Blocked by CCBs (-dipine)  Non-DHP (Verapamil, Diltiazem) (c) Voltage-gated K channels  Blocked by class III antiarrhythmic (Aminodarone)  Sulfonylureas – Type 2 DM ; insulin secretagogues 2) Enzymes  MAO (Moclobemide, Phenelzine, , Isocarboxazide, Tranylcypromine Selegeline) MPITS M – Selective MAOA inhibitors PIT  Non selective S  Selective MAOB inhibitors  COMT (-capones)  management in PD  ACE (-prils) –aka Kininase  COX (NSAIDs)  AChe (Organophosphates) 3) Carrier Molecules (Na-K ATPase, K-H pump, Re-uptake 1)  Na-K ATPase pump (Digoxin)  K-H ATPase pump (proton pump inhibitors; -prazoles 4) Receptors Receptors  A molecule to which a drug binds to bring about a change in function of the biologic system  Functional macromolecular component of a cell w/ a specific stereochemical configuration w/ which a ligand interacts in a lock & key fashion initiating a chain of biochemical events that leads to a therapeutic effect  Receptor site  Specific region of the receptor molecule to which the drug binds  Receptor affinity of the drug  a factor that will determine the number of drug-receptor complexes formed.  Inert binding molecule or site  A molecule to which a drug may bind without changing any function Spare receptor  Receptor that does not bind drug when the drug concentration is sufficient to produce maximal effect; present when Kd > EC50  Effector  Component of a system that accomplishes the biologic effect after the receptor is activated by an agonist; often a channel or enzyme molecule Type I (Ionotropic) receptors; 9ligand-gated ion channels)  Channel linked receptors  Controls movement of ions in & out the cell  Effect seen in milliseconds Ganglionic blockers, Nn Examples: Trimethapan o Nicotinic receptors (ligand-gated Na channel) Mecamylamine Benzodiazipine  Frequency Hexamethoprim Phenobarbital  Duration Neuromuscular blockers, Nm o Inhibited by NMBs & ganglionic blockers succinylcholine o GABAA receptors (CI channel) o Inhibitory NT o Facilitates iflux of CI inons resulting to hyperpolarization o Stimulated by benzodiazepines, barbiturates) Type II (Metabotropics) receptors (Signal transduction pathway or effector system)  7-transmembrane spanning receptors (serpentine receptors)  G protein linked Gs  activate adenylyl cyclase: increase cAMP or the release of secondary messenger  Beta receptors “Kiss & Kick” B1  increase contraction rate (heart) 1- Gq M1-Gq B2  bronchodilation (lungs) 2- Gi M2-Gi Gi  inhibit adenylyl cyclase; decreases cAMP 1-Gs M3-Gq Alpha-2, 5-HT1A , muscarinic, histamine receptors Go  unknown 2-Gs Gq Increase phospholipase C activity (splits Phospatidylinositol 4,5-bisphosphate); increase IP3, DAG, & cytoplasmic Ca2+ Ex, alpha-1 receptors, muscarinic Gt  increase cGMP phosphodiesterase: decrease in cGMP  Effects seen in seconds Type III (Enzyme-linked) receptors  translocation of glucose trensportation  Tyrosine kinase (insulin)  Guanylyl cyclase (cGMP as 2nd messenger)  Conversion of GTP to GMP DNA DNA RNA CHON MAOi  Involved in the action of NO  Effects seen in minutes DNA synthesis Transcription Translation  Example: o Insulin receptors o ANP receptor (Atrial natiuretic peptide) Type IV (Gene-transcription-linked) receptors  Nuclear or Cytoplasmic receptors  Effects seen in several hours  Examples o Steroid receptors (glucocorticoids, minercorticoids) o Thyroid hormone receptors o Sex hormones Type I, II, III (located in the cell membrane) Type IV (cytoplasm/ nucleus) Properties of Receptors: (a) Saturability  a finite number of receptors per cell, or per weight of tissue or protein is present as revealed by a saturable binding curve (b) Specificity  Lock & key fashion of drug-receptor interaction  Dugs should be structurally complementary to the receptor (c) Reversibility  The drug should bind to receptors then dissociate in its non-metabolized form This distinguishes receptor-drug interaction from enzyme-substrate interactions Drug-Receptor Interaction/ Drug protein target  Affinity  ability to bind to a receptor  Intrinsic activity  ability to generate a series of biochemical events leading to an effect/ biological changes Mechanism of Drug Action: Agonist  binds and causes a response (A drug that activates its receptor upon binding)  whose responses resembles the effect of the endogenous ligands. interact w/ specific cellular constituents, known as receptors, and elicit an observable biological response have both affinity for the receptor & intrinsic activity Example: Bethanecol directly stimulates cholinergic receptors & is thus an agonist  Full Agonist  produces all the expected effect of the binding to a receptor to the target protein Example: Morphine – opioid receptor  Partial Agonist  have no intrinsic activity but have affinity  cause opposite effect produces some of the expected effect  Interact w/ the same receptors as full agonist; however their affinity for the elicit the same maximum response  Have lower intrinsic activity than full agonist; however their affinity for the receptor can be greater than , or less than, or equal to that of full agonist. Example: Nalbuphine (Nubaine) analgesic has no bradicardiac effect Inverse Agonist  a drug that inhibits baseline level of activity, in the absence of agonist)  a ligand which produces an effect opposite to that of an agonist occupying the same receptor Antagonist  Inhibit the actions of agonist Pharmacological Antagonist lack intrinsic activity & produce effects by competitively & noncompetitively inhibiting the action of the endogenous molecules of the receptors A drug that binds without activating its receptor and thereby prevents activation by an agonist a. Phamacologic – Pharmacodynamic Antagonists Produces an effect opposite that an agonist by binding to same receptor Epinephrine – Propanolol (B1 receptor) Organophosphate – atropine (M receptor) may be two types: Competitive Antagonist  act by interfering w/ binding of the endogenous ligand to the receptor as the agonist A pharmacologic antagonist that can be overcome by increasing the concentration of agonist in a reversible manner There is shift of the agonist log-concentration-effect curve to the right w/out a change in the slope or aplitude Example:Propanolol competes w/ catecholamines for binding w/ adrenergic B-receptor Tamoxifen competes w/ estrogen receptors fro binding w/ estradiol Noncompetitive Antagonsit (Irreversible)  acts by interacting w/ the non-ligand binding site of the receptor (e.g, through covalent modification), such that normal binding of the endogenous ligand to the receptor is irreversible inhibited (A pharmacologic antagonist that cannot be overcome by increasing agonist concentration) Example:  Monoamine Oxidase (MOA) inhibitors such as tranyl cypranine (Parnate) initially interact w/ MOA in a reversible manner but then form covalent adducts that irreversible inhibit MOA b. Pharmacologic – Pharmacokinetic Antagonist produce an effect opposite that of an agonist or reduce the effect of the agonist by modifying the agonist’s ADME Cholestyramine (bile acid binding resin)  Can also bind digitalis, warfarin & Vitamin ADEK (reduce absorption) Phenobarbital & Warfarin interaction  Enzyme inducer (phenol) reduces effects of warfarin c. Chemical Antagonist  react w/ one another, resulting in the activation of both compounds.  antagonize other drugs by direct chemical interaction [A drug that counters the effects of another by binding the agonist drug (not the receptor)] Example: The anticoagulant heparin, an acidic polysaccharide, is chemically antagonized by protamine, a basic protein, via an acid-base interaction. Chelating agents can be used as antidotes for metal poisoning Ethylenediaminetetraacetic acid (EDTA) chelates calcium & lead Penicillamine chelates copper Dimecaprol chelates mercury, gold, antimony, & arsenic Deferoxamine  Fe oversoe  d. Physiologic (Functional) Antagonist act independently at different receptor sites often yielding opposing action. (A drug that counters the effects of another by binding to a different receptor and causing opposing effects)  produce antagonistic physiological action through binding at separate/different receptors. The adrenergic & cholinergic nervous system frequently produce this type of antagonism Example:  Epinephrine & acetylcholine action the sympathetic & parasympathetic autonomic nervous system, respectively & their effects are antagonistic to each other.  Epinephrine = Bronchodilation (B2) + Vasodilation (A1)  Histamine = Bronchospasm + Vasodialtion Inc HR due to Atropine (M blocker) Dec HR due to B-blocker e. Partial Antagonist  inhibit the endogenous ligand from binding the receptor but possess some intrinsic activity Example: Nalorphine is partial antagonist for opiate receptor f. Neutralizing Antagonist  occurs when two drugs bind w/ each other to form a inactive compound Example: Digoxin- binding antibody used in digoxin overdose acts by sequestering the drug resulting in the formation of an inactive complex Types of Chemical Bonds; (Molecular aspects of Binding) a) Covalent  strongest bond (irreversible effects) b) Electrostatic  very common type due to the attraction between oppositely charged groups c) Hydrogen  a strong interaction which arises from the sharing of hydrogen atom between an acidic & basic groups d) Van der Waals  weak interaction between polar or nonpolar molecules e) Hydrophobic  major driving force for nonpolar drug or receptor binding site Regulation of Receptors: I. Downregulation/ desensitization/ refractoriness  may explain the development of tolerance to drugs  maybe homologous (receptor itself) or heterologous (include downstream proteins that participate in the signaling)  Downregulation vs. Desensitization (reversible after laps of time) II. Upregulation/ supersensitivity Dose- response relationship (dose-response curves) o Classical Receptor Occupancy Theory Ariëns and Stephenson: KA Response = f (ENtotal. Xa/ (Xa + Ka) A = R AR stimulus response is an equation showing Receptor Occupancy  is given by the Langmuir Adsorption Isotherm: [A]/([A]+ Kd) Relationship between occupancy where Kd= dissociation constant of drug-receptor complex of receptor & response to the Total Receptor-mediated stimulus: drug A × Efficacy × R receptor number A + Kd 1. Graded dose-response curve  shows the relationship between the degree of response w/ dose, ie lowering of BP (a) Efficacy  is the capacity to produce an effect  represents the ability of a drug to accomplish a specified effect o Ceiling effect  maximum achievable response o Ceiling Dose  minimum dose that produces the maximum effect (maximum allowable dose) (b) Potency  is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. reflects the amount of drug (the dose) required to cause an effect.  (EC50) dose that produces 50% of the maximum response. (c) Slope  degree of change in response w/ dose (d) Variability, in effectiveness of a drug given to the same Px at different times can be due to: o Physiological factors (circadian rhythm) o Pathological factors (disease states/ health status) o Drug-induced variation (receptor down-regulation) o Variation in a population of Px (Genetic/ environmental) 2. Quantal dose-response curve (shows how a population respond (quantal event) to a given dose; ie prevention of convulsion, arrhythmia, or death) plots the cumulative # of respondents may it be beneficial effect w/ increasing dose.  Selectivity of Drug Action The ratio (relationship) between the dose of a drug required to produce undesired effects (toxic or lethal) & the dose required to produce the desired effects (therapeutics) 1. Therapeutic Index  is a relative measure of the safety & effectiveness in laboratory studies.  used to indicate the ability of adrug to produce the desired therapeutic effect relative to a toxic effect.  TD50 (Median Toxic Dose) the minimum dose that is toxic of the population  ED50 (Median Effective Dose)  the minimum dose that is effective for 50% of the population 2. Margin of Safety  is more practical term to describe the relative safety & effectiveness  is the ratio of the:  TD0.1 (Minimal Toxic Dose)  the minimum toxic dose for 0.1% of the population  ED99.9 (Minimal Effective Dose)  the minimum effective dose for 99.9% of the population Variation in Drug Responsiveness:  Idiosyncracy (genetic differences which affects the drug metabolism)  Hyporeactive vs. Hyperreactive  Tolerance & Tachyphylaxis  Mechanism of variation in Drug Responsiveness  Alteration in the concentration of drug that reaches the receptor o Some may be predicted on the basis of age, weight, sex, disease state, or kidney & liver function of the px.  Variation in concentration of endogenous receptor ligand o Propanolol will markedly slow the HR of Px whose catecholamines are elevated (pheochromocytoma) but will affect the resting HR of a marathon runner  Alteration in number or function of receptor o Downregulation/ upregulation of receptors o May be used to explain withdrawals from long term use of drugs  Changes in components of response distal to receptor o Clinically, changes in these post receptor processes represent the largest & most important class mechanisms that causes variation in responsiveness. Principles of Pharmacokinetics Pharmacokinetics  The actions of the body on the drug, Processes: L  Liberation including absorption, distribution, metabolism, and A  Absorption D  Distribution elimination. M  Metabolism Elimination of a drug may be achieved by metabolism or by E  Excretion excretion. R  Response Transport Processes: Transport  mechanism of the drug which it moves across the cell membrane. 1. Passive Diffusion  Movement of molecules from region high to low (along concentration gradient;)  Non-energy requiring (no external energy)  Major absorption process of most drugs (Predominant transport process)  Slowest process (inversely proportional to the membrane thickness)  Important process for small lipophilic molecules  Ex: Aspirin Factors affecting process: Most Drugs are absorbed or transported by passive (a) Fick’s law of diffusion 𝑄 = 𝐴 × 𝑑 (𝐶1 – 𝐶2)/ℎ diffusion, which depends on: Where: -pKa value of the solution Q= flux (movement of molecules) -pH of the Solution A= surface area of membrane -Lipid solubility of the unionized form d= diffusion coefficient C1= higher concentration (soure) C2= lower concentration (destination) h= thickness of the semi-permeable membrane (b) Concentration gradient determines Permeability Coefficient the ratio of the number of molecules crossing per unit time to the concentration gradient (c) Particle size (d) Liposolubility degree of ionization (relationship of pKa, pH & form of the drug) partition coefficient 2. Carrier-mediated transport Features: (a) Saturability  Follows saturable kinetics (Michaelis-Menten, Enzyme kinetics)  Ex. ASA 600mg/day (0th order) (b) Selectivity  Carriers have a specific stereochemical configuration, & will only allow transport of molecules that have configuration that fit into the carries binding site (c) Subject to competition/ inhibition  Ex. Isoniazid & Vit B6  Must be taken hours apart (About 2-3 hrs)  Otherwise will compete for the carries & will inhibit each other (d) “poisoning” Example of carrier-mediated transports: (1) Active Transport  movement against concentration gradient (low to high)  requires energy (energy-consuming) The Ileum sac of Guinea Pig is used  fast transport process for testing of Active Transport.  important for polar molecules  Ex: Na-K ATPase pump (sodium pump) (2) Facilitated Transport  movement along concentration gradient  no energy required  Ex: Vit B12 (Cyanocobalamin), glucose uptake 3. Carrier Mediated Intestinal Transport 1.) Vesicular Transport  process of engulfing particles  doesn’t require aqueous solution to be absorbed  Ex: Sabin Polio Vaccine Forms: Phagocytosis  engulfment of large particles Pinocytosis  engulfment of small particles  cell drinking  energy requiring  important for large lipophilic molecules  Ex: Griseofulvin, Vit ADEK (these drugs must undergo micelle formation) Processes: Endocytosis Absorption of material across a cell membrane by enclosing it in cell membrane material and pulling it into the cell, where it can be released. Ex: Taking up of Glucose by the Insulin Receptor. Exocytosis  Expulsion of material from vesicles in the cell into the extracellular space  accomplished the primary mechanism of neurotransmitter release Permeation  Movement of a molecule (eg, drug) through the biologic medium Drug permeation Most drugs are administered at a site distant from their target tissue. To reach the target, they must permeate through both lipid and aqueous pathways. Movement of drugs occurs by means of aqueous diffusion, lipid diffusion, transport by special carriers, or by exocytosis and endocytosis  2.) Convective (Pore) transport  transport thru water filled pores Factors affecting transport: (a) Pore size (diameter is 7-10 A) allows passage of substances w/ MW around 150-400 (small substances only) (b) Charge of the pore lining (allows passage of ions w/ opposite charge) (c) Electrochemical gradient (same as concentration gradient) (d) Solvent drag- solvent may drag in ions or molecules through the channels 3. Ion-Pair Transport  mechanism by which you transport drug w/ large ions Note: Passive, Carrier-mediated, Convective transport (Drug must be in aqueous solution) Pinocytosis (drugs must be in micellar forms) Liberation  Dosage form to solution  Release of Drug from the Dosage form  should be in aqueous solution  dissolution (rate-limiting step)  highly modifiable\able process  For drugs to be absorbed they must be liberated from the dosage form & from an aqueous solution  Factors affecting liberation o Formulation dependent factors (Tablet hardness, dissolution, & disintegration)  Exceptions: Parenterals, Solutions Effects: 1. Formulation of salt alkali metal (soluble group) 2. Formulation of prodrug in-vitro  in-vivo Advantages: 1.) enhances drug absorption Example: enalapril (ester) esterase enalaprilat (carboxylic group) 2.) Facilitates the drug reaching its target site 3.) alter drug solubility chloramphenicol (water-solubility) chloramphenicol palmitate ( slightly water-solubility) 4.) Facilitate formulation of dosage form methylprednisolone  methylprednisolone acetate  methylprednisolone Na succilate (slightly H2O-soluble) (H2O-insoluble) (H2O-soluble) Depot phase  liberates the drug to slower rate Absorption  from site of administration to systemic circulation  is a physical phenomenon Kinetic  rate & extent of drug entry into the systemic circulation Physiologic  rate & extent of disappearance of drug from site of administration A drug may be absorbed physiologically but not pharmacokinetically (ex: Metoprolol) Factors affecting absorption:  Pharmaceutical factors (particle size, physical state of the drugs) chemical structure Ex: Aminoglycosides  the only bactericidal among protein synthesis inhibitor  polar drugs  side effect: nephrotoxicity variation in particle size Nature of crystalline form Polymorphism exist two or more crystalline forms  Amorphous  more soluble than crystalline  Crystalline Example: Insulin short acting = 30-90 minutes after administration = 100% amorphous Intermediate = NPH (Neutral Protamine of Hagedorn) = 5-6 hours = 30% amorphous + 70% crystalline Long = 12-24 hours = 100& crystalline Anhydrous vs. Hydrous more soluble less soluble hydrolysis resistant Tablet coating Ex: Enteric Coated  prevent GI irritation  protects drug from stomach aid  enhances absorption  Fick’s law of diffusion  Gastric Emptying Time (Factors that increase/ decrease GET) when gastric emptying time increase, Factors Influencing Gastric Emptying: the gastric emptying rate decreases, 1. Volume of Liquid intake the absorption rate decreases. 2. Type of Meal Factors GET (GER) Factors GET (GER) 3. Osmotic Pressure  High CHON/ fat  Spicy foods 4. Physical state of Gastric content 5. pH of the Stomach  Cold food  Extreme temp. of meal 6. Drugs to be taken  Gastric ulcers  Gastrectomy 7. Body position  Stress  Depression 8. Viscosity of stomach content  Vigorous exercise  Mild Exercise 9. Emotional States  Lying on the left side  Lying on right side 10. Disease State  Drugs (Antidiarrhea-  motility enhancing agents: 11. Presence of bile salts antimotility agents) metoclopramide 12. Exercise  Hunger domperidone 13. Age of a person cisapride]  Diabetes Mellitus Mechanism of Absorption of Drugs (in order of their importance): 1. Passive Diffusion Gastric-Emptying  rate limiting step for absorption of oral solution 2. Convective/Pore Transport 3. Active Transport  Dose size administered 4. Facilitated Transport  pH of the absorbing environment (affects ionization of the drug) 5. Ion pair Transport  area of the absorbing surface (lungs biggest SA, small intestines 6. Vesicular Transport  degree of perfusion  Physical factors that affect absorption  Blood flow  Surface area for absorption  Contact time Distribution  transport or net tansfer of drugs from the systemic circulation to the site of action describes the movement of drug molecules across different body compartment Physiologic Factors affecting distribution: Cardiac output: volume of blood pumped by the heart per minute  Px with CHF may have delayed drug effect due to poor distribution Regional blood flow  (% of CO that reaches specific tissue)  Fraction of the CO going to particular organs/ tissues  Organs w/ high RBF (liver (25%), kidney(25%), lungs(100%), brain)  Organs with low RBF (bone, adipose)  Capillary Permeability  Capillary delivery oxygenated blood to tissues; smallest vein two important parameters of drug distribution: o PB (Protein binding) o Vd (volume of distribution)  Protein Binding limits the access of drugs to certain body compartment  binding of the serum proteins  decreases distribution  Free form (unbound) can reach the site of action, metabolized, excreted  Bound form (serves as reservoir)  Examples of proteins & substrates o Albumin  weak acidic (dominant) o Alpha 1 glycoprotein  weak basic drugs o Globulin  binding formones  Significant protein binding= 80%; Penicillins have >97%PB  Significant of PB o Provide slow release form of a drug (repository, resulting to extended affect) o Limits access to certain body compartment o Can make the drug prone to drug-drug interaction  Examples of drugs with high protein binding: o Diazepam, Diditoxin, Indomethacin, Tolbutamine, Warfarin, Midazolam o These drugs cam compete w/ each other o Results to increase effect (toxicity) of the object drug o The known importance of protein binding: Transport function  reflected w/ drugs of low solubility in water Buffer function  to maintain a relatively constant concentration Drugs that are more than 90% bound to plasma proteins: - Amitryptilline - Chlorpromazine - Cloxacillin - Flurazepam - Lidocaine - Lorazepam - Naproxen - Phenylbutazone - Penicillin - Phenytoin - Propanolol - Warfarin Decrease Albumin Level: - Pregnancy - Nephrotic Syndrome - Trauma - Chronic Liver Disease - Burns Factors affect the protein binding drugs: - Pregnancy - - Hypoalbuminemia - - Uremia   Volume of distribution  is the hypothetical volume of fluid where drug is disposed the ratio of the amount of drug in the body to the drug concentration in the plasma or blood Extent of Distribution of drugs is effected by:  Plasma protein binding  pH Rate of Distribution of drugs is effected by:  Blood perfusion  Membrane permeaility  Hypothetical volume of body fluids necessary to dissolve a given amount of drug to a concentration equal to that in the plasma  Theoritical Volune  Application Vd 1. Loading Dose 𝑑𝑜𝑠𝑒 𝑉𝑑 = 𝐶𝑝 2. Predict the location of drug  Significance: o May be used to compute loading dose o Identification of most likely compartment of dictribution of a given drug  Correlation with body fluids: o Total body fluids = 60% of BW (Males) = 50-55% of BW (Females) o Intracellular fluids = 40% o Extracellular fluids = 20% *Water compartment Interstitial = 15%  where drugs can be found Intravascular = 5% 1. Plasma compartment o Approximate Volume of Distribution of a drug in an ADULT  high-molecular weight & Ex: For a 70 Kg Px highly protein bound o Total/Whole body fluids =40/42 L 2. ECF  low molecular weight & o Intracellular fluids = 25-30 L hydrophilic o Extracellular fluids = 10-20 L 3. Total body water o Interstitial = 10.5 L  low molecular/ hydrophobic o Intravascular = 3.5 L o Circulatory system = 5mL  Examples of drugs with high Vd:  Atropine, CHloroquine, Digoxin, Fluoxetine, Imipramine & TCAs, beta blockers  Examples of Drugs with low Vd:  Chlorpropamide, Furosemide, Tolbutamine, Valproic Acid, Warfarin  Significance: Management of Toxicities/ drug overdose  Drugs w/ low Vd= hemodialysis (alternative treatment)  Drugs w/ high Vd = hemodialysis (useless) (Katzung) Apparent Volume of Distribution and Physical Volumes Apparent Volume of Distribution (Vd) is an important pharmacokinetic parameter that reflects the above determinants of the distribution of a drug in the body. Vd relates the amount of drug in the body to the concentration in the plasma. Average values for some physical volumes within the adult human body. Compartment Volume (L/kg BW) Plasma 0.04 Blood 0.08 Extracellular 0.2 Total Body water 0.6 Fat 0.2-0.35  Distribution phase  The phase of drug movement from the site of administration into the tissues  The Larger the Volume of Distribution, the more extensive the distribution Metabolism aka biotransformation  lipophilic into more water-soluble or polar, pharmacologically inactive, & readily excretable form Objectives: conversion of xenobiotics to a form less toxic, polar & readily excretable. Exceptions: o Inactive (prodrug) to active form Kinetic of Metabolism: o Phenacetin to Acetaminophen 1st order  concentration dependent kinetic o Prontosil to Sulfadiazine imporatant in maintenance of your steady o Enalapril to Enalaprilat state o Allopurinol to alloxanthine constant fraction of a drug o Active to active metabolites Example: 100mg80mg64 …… 20% o Diazepam to Nordiazepam to Oxazepam 0th order  concentration independent o Atracurium to laudanosine  increase in the rate of metabolism o Eserine to Rubreserine saturable kinetic/Michaelis-Menten o Codeine to Morphine constant amount o Non-toxic to toxic form Example: 100mg80mg60 …… 20mg o Malathion to Malaoxon o Acetaminophen(Paracetamol) to NAPQI Location: o Primarily in the liver o Kidney (Imepenem metab by dihydropeptides in the kidney) o Intestines Drugs that are o Blood Extensively First-pass metabolism 𝐶𝐿𝑙𝑖𝑣𝑒𝑟 Metabolized by First Extraction ratio : 𝐸𝑅 = ; where Q is hepatic blood flow (about 90L/hr in a 70kg patient) Pass Effect: 𝑄 Systemic bioavailability : 𝐹 = 𝑒𝑥𝑡𝑒𝑛𝑡 𝑜𝑓 𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑓 × (1 − 𝐸𝑅) -Lidocaine Drugs with extensive FPE (high ER): propanolol, catecholamine, meperidine, morphine, pentazocine -Isoproterenol First-pass Effect (presynaptic elimination) describes the phenomenon whereby drugs may be metabolized -Nitroglycerin (not chemically degraded) following absorption but before reaching systemic circulation -Morphine Hepatic first-pass effect  may occur following P.O. & deep rectal administration -Meperidine  may be avoided by using sublingual & buccal routes of administration -Prpoxyphene Pulmonary first-pass effect  cannot be avoided by intravenous, buccal or sublingual routes. -Propanolol Phases (Matabolic Reactions) -Salicylamide 1. Phase I  Reactions that convert the parent drug to a more polar (water-soluble) or more reactive -Entazocined product by unmasking or inserting a polar functional group such as –OH, –SH, or –NH2  usually involves conversion of drugs to active from by addition or unmasking of a functional group.  Oxidation, Reduction, Hydrolysis dominant among phase I reaction Phase I Drug-Metabolizing Reactions (Functionalization Reaction A. Oxidation – dominant Reaction Type Typical Drug Substrates Oxidations, CYP450 dependent  Hydroxylation Aromatic Hydroxylation Phenobarbital, Propanolol, Phenytoin, Warfarin, Ethinyl Estradiol Aliphatic Hydoxylation Pentobarbital, Chlorpromazine, Ibuprofen  N-dealkylation Caffeine, Morphine, Theophylline  O-dealkylation Codeine, Dextromethorphan, Indomethacin  N-oxidation Meperidine, Acetaminophen, Nicotine  S-oxidation Chlorpromazine, Cimetidine, Thioridazine, Omeprazole  Deamination Amphetamine, Diazepam A partial list of drugs that significantly INDUCE P450-mediated drug metabolism in humans: CYP Family Important Inducers Drugs Whose Metabolism Is Induced Induced 1A2 Benzo[a]pyrene (from Acetaminophen, Clozapine, Haloperidol, Theophylline, Phenobarbital, Rifampin, tobacco smoke), Omeprazole Tricyclic Antidepressants, (R)-Warfarin, Tamoxifen Carbamazepine, Charcoal-broiled foods, Cruciferous vegetables, Omeprazole 2C9 Barbiturates, Especially Barbiturates, Celecoxib, Chloramphenicol, Doxorubicin, Primidone, Rifampin Phenobarbital, Phenytoin, Ibuprofen, Phenytoin, Chlorpromazine, Steroids, Tolbutamide, (S)-Warfarin 2C19 Carbamazepine, Diazepam, Phenytoin, Topiramate, Tricyclic Antidepressants, (R)-Warfarin Phenobarbital, Phenytoin, Rifampin 2E1 Ethanol, Isoniazid Acetaminophen, Enflurane, Ethanol (Minor), Halothane 3A4 Barbiturates, Antiarrhythmics, Antidepressants, Azole Antifungals, Phenytoin, Rifampin, Carbamazepine, Pioglitazone, St. John's Wort Benzodiazepines, Calcium Channel Blockers, Corticosteroids, Efavirenz, Cyclosporine, Delavirdine, Doxorubicin, Efavirenz, Erythromycin, Estrogens, HIV Protease Inhibitors, Nefazodone, Paclitaxel, Proton Pump Inhibitors, HMG-Coa Reductase Inhibitors, Rifabutin, Rifampin, Sildenafil, Ssris, Tamoxifen, Trazodone, Vinca Alkaloids  A partial list of drugs that significantly INHIBIT P450-mediated drug metabolism in humans. CYP Family Inhibitors Drugs Whose Metabolism Is Inhibited Inhibited 1A2 Cimetidine, Fluoroquinolones, Acetaminophen, Clozapine, Haloperidol, Theophylline, Tricyclic Grapefruit Juice, Macrolides, Antidepressants, (R)-Warfarin Isoniazid, Zileuton 2C9 Amiodarone, Chloramphenicol, Barbiturates, Celecoxib, Chloramphenicol, Doxorubicin, Cimetidine, Isoniazid, Metronidazole, Ibuprofen, Phenytoin, Chlorpromazine, Steroids, Tolbutamide, Ssris, Zafirlukast (S)-Warfarin 2C19 Fluconazole, Omeprazole, Ssris Diazepam, Phenytoin, Topiramate, (R)-Warfarin 2D6 Amiodarone, Cimetidine, Quinidine, Antiarrhythmics, Antidepressants, Beta-Blockers, Clozapine, Ssris Flecainide, Lidocaine, Mexiletine, Opioids 3A4 Amiodarone, Azole Antifungals, Antiarrhythmics, Antidepressants, Azole Antifungals, Cimetidine, Clarithromycin, Benzodiazepines, Calcium Channel Blockers, Cyclosporine, Cyclosporine, Diltiazem, Delavirdine, Doxorubicin, Efavirenz, Erythromycin, Estrogens, HIV Erythromycin, Fluoroquinolones, Protease Inhibitors, Nefazodone, Paclitaxel, Proton Pump Grapefruit Juice, HIV Protease Inhibitors, HMG-Coa Reductase Inhibitors, Rifabutin, Rifampin, Inhibitors, Metronidazole, Quinine, Sildenafil, Ssris, Tamoxifen, Trazodone, Vinca Alkaloids Ssris, Tacrolimus Suicide inhibitors are drugs that are metabolized to products that irreversibly inhibit the metabolizing enzyme.  Ethinyl Estradiol  Norethindrone CYP3A4 responsible for the highest  Spironolactone fraction of clinically important  Secobarbital drug interactions resulting from  Allopurinol metabolism  Fluroxene  Propylthiouracil Oxidations, CYP450 Independent  Amine Oxidation (MAO) Epinephrine  Dehydrogenation Aldehyde, Chloral Hydrate, Ethanol, Olefins, Aromatic B. Reduction Reductions  Nitro-Reduction Chloramphenicol  Carbonyl-Reduction Naloxone C. Hydrolysis Hydrolyses  Esters Aspirin, Clofibrate, Procaine, Succinylcholine  Amides Indomethacin, Lidocaine, Procainamide 2. Phase II (Conjugation Reactions)  increase water solubility by conjugation of the drug molecule w/ a polar moiety such as glucuronate, acetate, or sulfate  almost always involved in the inactivation of drug & formation of its polar form.  allows attachment to small, polar & ionizable endogenous compounds  allow the termination or attenuation of a biologic activity serve to protect the body against chemically reactive compounds or metabolites Reaction Type Typical Drug Substrates (a) Glucuronidation Acetaminophen, Diazepam, Digoxin, Morphine, Sulfamethiazole, Chloramphenicol (kernicterus) Expression of glucoronosyl transferase is inducible (Phenobarbital)  Available source of D-glucuronic acid  Responsible for functional groups that can combine enzymatically w/ glucuronic acid  Require an active center as the site of conjugation (b) Acetylation Clonazepam, Dapsone, Isoniazid, Mescaline, Sulfonamides, Hydralazine, Procainamide Expression of glucoronosyl transferase is subject to genetic polymorphism Fast Acetylators Slow Acetylators -Eskimos -Egyptians -Orientals (Filipinos/Asians) -Mediterranean Jews (c) Glutathione Ethacrynic Acid, Reactive Phase I Metabolite of Acetaminophen Conjugation Neutralizes chemically reactive substances  Back-up mechanism for paracetamol toxicity (d) Glycine Conjugation Deoxycholic Acid, Nicotinic Acid (Niacin), Salicylic Acid (e) Sulfation Acetaminophen, Estrone, Methyldopa  Only phase II reaction present in neonates (only well-developed metabolic pathway in neonates) (f) Methylation Dopamine, Epinephrine, Histamine, Norepinephrine, Thiouracil  Important in biosynthesis of many endogenous substances like epinephrine & melatonin  Constitutes only a minor pathway for conjugating drugs or xenobiotics, Paracetamol (Acetaminophen) sulfation NAPQI glutathione conj. Mercapturic acid N-acetylparaquinoneimine (hepatotoxic form) Enzyme inhibiton-induction Enzyme-inducers  stimulate the release of CYP450 Consequences: Low therapeutic levels of active drug ( decrease efficacy) Enzyme Inhibitors Enzyme Inducers Prodrug (increase in efficacy) “sickfaces.com” “GPP PARK Sa Mall” Toxic metabolite (increase toxicity)  Sodium valproate  Griseofulvin Cross-induction  stimulated by auto & foreign induction  Isoniazid  Phenobarbital (Barbiturates) Foreign-induction  stimulates another drugs  CImetidine  Phenytoin Auto-induction  stimulate its own metabolism (Carbamazepine)  Ketoconazole  Phenylbutazone Enzyme-inhibitors  competitive inhibition  Fluconazole  Alcohol (chronic) Consequences: Active object drug (increase efficacy; intoxicity)  Alcohol (Acute)  Rifampicin Prodrug (decrease in efficacy)  Ciprofloxacine  Carbamazepine Toxic metabolite (decrease toxicity)  Erythromycin  Sulfonlurea  Sulfanamide  Meprobamate  Chloramphenicol  Omeprazole Herbs: St. John’s wort  Metronidazole  Herbs:  Grape fruit  Valencia oranges Genetic Polymorphism  variation in the DNA sequence that is present at an allele frequency of 1% or greater in apopulation  variation in the expression of enzymes (rapid/slow acetylators, CYP polymorphism) 1. CYP 2D6 polymorphism (increased risk of cardiotoxicity)  Thioridazine & antidepressants (Poor Debrisoquin Metabolizer) CYP 2D6  most studied 2. Acetylation  HIPS: Hydralazine, Isoniazid, Procainamide, Sulfonamide(causes Steven Johnson Syndrome (very notorious in causing SLE) Isoniazid  peripheral neuropathy; Isoniazid toxicity (treated with Vitamin B6) Genetic Polymorphism variation in the expression of enzymes EM – Extensive Metabolizers PM – Poor Metabolizers UM – Ultra Rapid Metabolizers NAT2  N-acetyltransferase HIP: hydealazine, INH, Procainamide  cause Drug-induced SLE Fast acetylators: Asia – Extensive Metablozers Slow Acetylators: Caucasian – Poor Metabolizers CYP2D6 Tamoxifen CYP2D6 PM -  effect Endoxifen UM -  effect Codeine CYP2D6 PM -  effect Morphine UM -  effect Sites of Biotransformation/ Metabolism  Liver  Stomach  Intestine  Lungs  Skin  Kidney Factors affecting drug Metabolism Age Differences Species & Strain Differences Hereditary or Genetic Factors Sex Differences Enxyme Induction Enzyme Inhibition Regioselectivity  denotes the selective metabolism of two or more similar functional groups, or two or more similar atoms that are positioned in different regions of a molecules Elimination  final loss of the drug from the body; constitutes metabolism & excretion General Requirements: water-soluble (polar) Routes of excretion: Renal, Biliary, Lungs, Skin, Mammary, Intestinal Total body clearance  drug elimination rate divided by plasma drug concentration Renal drug excretion major route for polar, water-soluble, drug w/ lo MW (80mL/min CLCr(Male)= ( 140Age ) BW in Kg Mild Renal Function 50-80 mL/min Note: if unit given is 72 x Plasma Cr in mg/dL Moderate Renal Function 30-50 mL/min mol/L (convert to CLCr(Female)= 0.85 (CLCr of male) Severe Renal Function Enflurane > Isoflurane > Sevoflurane> Desflurane> Nitrous Oxide Intavenous  for rapid induction of anesthesia; maintained with inhalational agent Barbiturates  induce sedation Thiopental (Pentothal®, Pentobrim®) POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors PHARMACOLOGIC EFFECTS: circulatory and respiratory depression; decrease intracranial pressure Thioamylal TOXICITY: extensions of CNS depressant actions; additive CNS depression with many drugs Methohexital Theopental  can only be used to induce anesthesia but not to maintain anesthesia Benzodiazepines used for sedation ; reduce anxiety & seizure; Midazolam premedication when large doses of local anesthetics must be administered to reduce seizure POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors PHARMACOLOGIC EFFECTS: less depressant than barbiturates SE: Postoperative respiratory depression reversed by flumazenil Imidazole POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors Etomidate PHARMACOLOGIC EFFECTS: Minimal effects on CV and respiratory functions SE: No analgesia, pain on injection (may need opioid), myoclonus, nausea, and vomiting Phenols for rapid onset, short duration hypnosis Propofol (Diprivan®, Fresofol®) POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors PHARMACOLOGIC EFFECTS: Propofol: vasodilation and hypotension; negative inotropy. Fospropofol Fospropofol water-soluble SE: Propofol: Hypotension (During Induction), Cardiovascular Depression  Propofol (Diprivan , Fresofol®)  a preparation containing soybean oil & egg phospholipid ® Dissociative provides dissociative anesthesia (analgesia, amnesia without loss of consciousness) Ketamine POSSIBLE MOA: Blocks excitation by glutamate at NMDA receptors PHARMACOLOGIC EFFECTS: Analgesia, amnesia and catatonia but "consciousness" retained; (Ketalar®, Ketaject®, cardiovascular (CV) stimulation Ketamax®, Quetanex®) SE: Increased intracranial pressure; emergence reactions; Distortion of reality & terrifying dreams Opioids POSSIBLE MOA: Facilitate GABA-mediated inhibition at GABAA receptors Fentanyl PHARMACOLOGIC EFFECTS: Marked analgesia, respiratory depression SE: Respiratory depression—reversed by naloxone Alfentanil Remifentanil Nitrous Oxide + Droperidol + Fentanyl = ―neuroleptanesthesia‖ Morphine Local Anesthetics  Common MOA: Inhibition of Voltage-Gated Sodium Channel  NOTE: CO-administered with vasoconstrictor Epinephrine (1: 100,000)  COMMON SE: lightheadedness, dizziness, seizures, shivering, respiratory depression, coma, bradycardia, hypotension  All Local Anesthetics are vasodilators, except for COCAINE (vasoconstrictor) Amides MOA: Blockade of Na+ channels slows in nerves, then prevents axon potential propagation. Articaine (Ubistesin®) provides analgesia without loss of consciousness CLINICAL APPLICATIONS: Analgesia via topical use, / injection (perineural, epidural, subarachnoid); Bupivacaine (Marcaine®, Sensorcaine®, Senpivac®) rarely IV Etidocaine (Duranest®) SE: CNS: excitation, seizures Levobupivacaine (Sensibloq®) CV: vasodilation, hypotension, Lidocaine (Xylocaine®) arrhythmias (bupivacaine) Bupivacaine  most cardiotoxic Mepivacaine (Carbocaine®, Mepivastesin®) Lidocaine  most neurotoxic when given as a spinal anesthetic Prilocaine (Citanest®, Emla®)  has a relatively longer half-life Ropivacaine (Naropin®)  DOC for Ventricular Tachycardia Prilocaine  can predispose to the development of methemoglobinemia when given in large doses during regional anesthesia -Ortho-Toluidine  metabolite of Prilocaine  when formed in the body in significant amounts can cause oxidation of the iron I hemoglobin to the ferric form Esters MOA: Blockade of Na+ channels slows in nerves, then prevents axon potential propagation Benzocaine (Americaine®, United Home Burn Ointment®) provides analgesia without loss of consciousness Additional MOA of Cocaine: Intrinsic Sympathomimetic Actions Cocaine CLINICAL APPLICATION/S: Analgesia, topical only for cocaine and benzocaine Procaine (Novocaine®) SE: CNS: excitation, seizures; Cocaine vasoconstricts Tetracaine (Pontocaine®) When abused has caused hypertension and cardiac arrhythmias Chloroprocaine (Nesacaine®) Tetracaine, Procaine, & Chloroprocaine  are para-amino benzoic acid derivatives Proparacaine (Alcaine®)  Allergic reaction is most likely to occur Dibucaine (Nupercainal®) Butylcholinesterase  is responsible for the metabolism of ester-type local anesthetics  The degree of anesthetic activity of an ester is higher if the acid group is Aromatic.  Drugs of Abuse CNS Stimulants Caffeine (1,3,7-trimethylxanthine) MOA: inh. phosphodiesterase  inc. cAMP inc. Adrenergic Action Theophylline (1,3-dimethylxanthine) Theobromine (3,7-dimethylxanthine) Nicotine For smoking cessation: Nicotine Polacrilex gum (Nicorrete®) Clonidine (Catapress®) Bupropion (Wellbutrin®, Zyban®) Vareniclinen (Champix®) Amphetamines: Methylphenidate (Ritalin®, Concerta®) Methamphetamine (shabu, ice, meth) Ecstacy (Metylenedioxymethamphetamine/ MDMA) Phentermine (Ionamine®, Duromine®) Bangkok pills (Phentermine+ Fenflurane) Cocaine (Crack) CNS depressants Ethanol/ Ethyl Alcohol ANTI-ALCOHOLISM: Disulfiram (Antabuse®) IMPORTANT SE: Wernicke-Korsakoff Syndrome Benzodiazepines Opioids Heroin Morphine Hallucinogens Phencyclidine (PCP, “angel dust”) Lysergic acid diethylamide (LSD) Marijuana (delta-9-tetrahydrocannabinol , 9-THC) Drugs Used to Treat Dependence and Addiction Subclass Mechanism of Effects Clinical Applications Pharmacokinetics, Toxicities, Action Interactions Opioid antagonists Naloxone Antagonists of Reverse or block effects of Naloxone: opioid overdose Naloxone: Short half-life (1-2 h) Naltrexone opioid receptors opioids Naltrexone: treatment of alcoholism Naltrexone: Half-life like morphine (4 h) Synthetic opioid Methadone Slow-acting agonist Acute effects like Substitution therapy for opioid addicts Variable half-life at opioid receptors morphine Toxicity: Like morphine re acute and chronic effects including withdrawal Partial -receptor agonist Buprenorphine Partial agonist at Attenuates acute effects of Substitution therapy for opioid addicts Long half-life (>40 h); formulated with opioid receptors morphine and other strong nalorphine to avoid illicit IV use opioids N-receptor partial agonist Varenicline Agonist at ACh-N Blocks "rewarding" effects Smoking cessation Nausea and vomiting, psychiatric receptor (22) of nicotine changes, seizures in high dose subtype Benzodiazepines Oxazepam Modulators of Enhance GABA functions Attenuate withdrawal symptoms Half-life 4-15 h; lorazepam kinetics not Lorazepam GABAA receptors in CNS including seizures from alcohol and affected by liver dysfunction other sedative-hypnotics NMDA receptor antagonist Acamprosate Antagonist at May block synaptic Treatment of alcoholism (in Allergies, arrhythmias, variable BP effects, glutamate plasticity combination with counseling) headaches, and impotence; hallucinations NMDA receptors in elderly Cannabinoid receptor agonist Rimonabant Agonist at CB1 Decrease GABA and Treatment of obesity; off-label use for Major depression; increased suicide risk receptors glutamate release in CNS smoking cessation XIII. CHEMOTHERAPEUTIC DRUGS CANCER  uncontrolled cell proliferation  tumor/ neoplasm Malignant Tumor/ Cancer  metastasize or spread to other parts of the body Benign Tumor/ Cancer  does not metatasize CANCER DRUGS  CELL CYCLE th Cancer Chemotherapy Drugs (Katzung 9 ed) Subclass Mechanism of Action Clinical Applications Acute Toxicities Chronic Toxicities Alkylating agents Cyclophosphamide Forms DNA cross-links, resulting Breast Cancer, Nausea &Vomiting Myelosuppression, in inhibition of DNA synthesis and Ovarian Cancer, Alopecia, function Non-Hodgkin's Lymphoma, Hemorrhagic Cystitis Chronic Lymphocytic Leukemia, Neuroblastoma Other major alkylating agents: Mechlorethamine, procarbazine, busulfan carmustine, lomustine, dacarbazine Platinum analogs: Cisplatin, carboplatin, oxaliplatin Antimetabolites Methotrexate Inhibits DHFR, resulting in Breast Cancer, Head &Neck Mucositis, Myelosuppression inhibition of synthesis of Cancer, Primary CNS Diarrhea thymidylate, purine nucleotides, Lymphoma, Non-Hodgkin's serine, and methionine Lymphoma, Bladder Cancer, Choriocarcinoma 6-Mercaptopurine Inhibits de novo purine synthesis Acute myelogenous leukemia Nausea & Vomiting Myelosuppression, Immunosuppression, Hepatotoxicity 5-Fluorouracil Inhibits thymidylate synthase, and GI Cancers, Nausea, Myelosuppression, its metabolites are incorporated Breast Cancer, Mucositis, Neurotoxicity into RNA and DNA, all resulting in Head & Neck Cancer, Diarrhea inhibition of DNA synthesis and Hepatocellular Cancer function and in RNA processing Other antimetabolites: Cytarabine, gemcitabine Plant Alkaloids (Cell cycle-specific agent) Vinca alkaloids Vincristine Interferes with microtubule Acute Lymphocytic Leukemia, None Neurotoxicity w/ Peripheral function, resulting in impaired Hodgkin's & Non-Hodgkin's Neuropathy, mitosis Lymphoma, Paralytic Ileus, Wilms' Tumor, Myelosuppression, Neuroblastoma Alopecia, Inappropriate ADH Secretion Other vinca alkaloids: Vinblastine, vinorelbine Cantharatine  is the indole-containing moiety of the antitumor vinca alkaloids idolated from periwinkle Catharanthus roseus Vindoline  is the indoline-containing moiety Podophyllotoxins Etoposide Analogue of Podophyllotoxin, Lung Cancer, Nausea, Alopecia, inhibits topoisomerase II, resulting Non-Hodgkin's Lymphoma, Vomiting Myelosuppression in DNA damage Gastric Cancer first choice tx for small-lung cancer Other podophyllotoxins: Teniposide Camptothecins Topotecan Inhibits topoisomerase I, resulting Small Cell Lung Cancer, Nausea, Myelosuppression in DNA damage Ovarian Cancer Vomiting, Diarrhea Other camptothecins: Irinotecan Taxanes Paclitaxel Interferes with microtubule Breast, Lung, Nausea, Myelosuppression, function, resulting in impaired Ovarian, Vomiting, Peripheral Sensory Neuropathy mitosis Gastroesophageal, Hypotension, Prostate, Bladder, Arrhythmias, Head & Neck Cancers Hypersensitivity Other taxanes: Docetaxel Antibiotics Anthracyclines Doxorubicin Oxygen free radicals bind to DNA Lymphomas, Nausea, Alopecia, (Adrianamycin®) causing strand breakage; inhibits Myelomas, Arrhythmias Cardiomyopathy, topoisomerase II; intercalates into Sarcomas, Myelosuppression, DNA Breast, Lung, Ovarian And Cardiotoxic Thyroid Cancers Dactinomycin Intercalates in DNA Wilms’ Tumor, Nausea&Vomiting, Myelosuppression, (actinomycin D) Ewing’s Sarcosoma, Anorexia, Alopecia, Rhabdomyosarcosoma Erythema & Tissue Bone Marrow Depression, (Childhood Tumors) Injury Other anthracyclines: Daunorubicin, idarubicin, epirubicin, mitoxantrone Bleomycin  can cause Pulmonary Toxicity (Pulmonary Fibrosis) Other antitumor antibiotics: Bleomycin, mitomycin, Dactinomycin  from S. verticillus  occurs naturally as a blue copper complex Monoclonal Antibodies Tyrosine kinase inhibitors Imatinib Inhibits bcr-abl tyrosine kinase Chronic Myelogenous Nausea, Fluid Retention w/ Ankle & Periorbital and other receptor tyrosine Leukemia(CML), Vomiting Edema, kinases GI Stromal Tumor Diarrhea, Myalgias, Congestive Heart Failure Other tyrosine kinase inhibitors: Dasatinib, nilotinib Growth factor receptor inhibitors Trastuzumab Inhibits the binding of EGF to the HER-2/neu receptor + breast Nausea, vomiting, Cardiac dysfunction (Herceptin®) HER-2/neu growth receptor cancer chills, fever, (Metastatic Breast cancer) headache Other growth factor receptor inhibitors: Cetuximab, panitumumab, gefitinib, erlotinib Vascular endothelial growth factor (VEGF) inhibitors Bevacizumab Inhibits binding of VEGF to its Colorectal, Breast, Hypertensin, Arterial Thromboembolic Events, receptor, resulting in inhibition of Non-Small Cell Lung, Infusion Reaction Gastrointestinal Perforations, Wound tumor vascularization Renal Cancer Healing Complications, Proteinuria Hormones Hormone agonists Prednisone most commonly used glucocorticoid in cancer chemo. Ketone Reduction  involved in biotransformation of prednisone to prednisolone MOA: May trigger apoptosis. May even work on non-dicing cells. CLINICAL USE: Many inflammatory conditions, organ transplantation, hematologic cancers SE/ TOXICITY: Adrenal Suppression, Growth Inhibition, Muscle Wasting, Osteoporosis, Salt Retention, Glucose Intolerance, Behavioral Changes Hormone antagonists Tamoxifen, MOA: Estrogen antagonist actions in breast tissue and CNS; estrogen agonist effects in liver and bone Raloxifene CLINICAL USE: Prevention and adjuvant treatment of hormone-responsive breast cancer SE/ TOXICITY: Hot Flushes, Thromboembolism, Endometrial Hyperplasia Other hormonal antagonists: Aromatase inhibitors, GnRH agonist and antagonists, androgen receptor antagonists (see Chapter 40) DHFR, dihydrofolate reductase; EGF, epidermal growth factor; GnRH, gonadotropin-releasing hormone; VEGF, vascular endothelial growth factor. I. PRINCIPLES OF ONCOLOGY. Cancer refers to a heterogeneous group of diseases caused by an impairment of the normal functioning of genes, which leads to genetic damage. A. Characteristics of cancer cells. 1. Carcinogenesismechanism of how many cancers occur is thought to be a multistage, multifactorial process that involves both genetic and environmental factors. a. Initiation first step involves the exposure of normal cells to a carcinogen, producing genetic damage to a cell. b. Promotionenvironment becomes altered to allow preferential growth of mutated cells over normal cells. The mutated cells become cancerous. c. ProgressionIncreased proliferation of cancer cells allows for invasion into local tissue andmetastasis. 2. Types of cancer. Tumors can be benign or malignant. Benign tumors are generally slow growing, resemble normal cells, are localized, and are not harmful. Malignant tumors oft en proliferate more rapidly, have an atypical appearance, invade and destroy surrounding tissues, and are harmful if left untreated. Malignant cancers are further categorized by the location from where the tumor cells arise. a. Solid tumors. Carcinomas are tumors of epithelial cells. These include specifi c tissue cancers (e.g., lung, colon, breast). Sarcomas include tumors of connective tissue such as bone (e.g., osteosarcoma) or muscle (e.g., leiomyosarcoma). b. Hematological malignancies. Lymphomas are tumors of the lymphatic system and include Hodgkin and non-Hodgkin lymphomas. Leukemias are tumors of blood-forming elements & classified as acute or chronic and myeloid or lymphoid. B. Incidence.The most common cancers are breast, prostate, and colorectal. The leading cause of cancer death is lung cancer. C. Cause. Many factors have been implicated in the origin of cancer. Some of these factors are as follows: 1. Viruses, including Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human papillomavirus (HPV) 2. Environmental and occupational exposures, such as ionizing and ultraviolet radiation and exposure to chemicals, including vinyl chloride, benzene, and asbestos 3. Lifestyle factors, such as high-fat, low-fi ber diets and tobacco and ethanol use 4. Medications, including alkylating agents and immunosuppressants 5. Genetic factors, including inherited mutations, cancer-causing genes (oncogenes), and defective tumor-suppressor genes D. Detection and diagnosis are critical for the appropriate treatment of cancer. Earlier detection may improve response to treatment. 1. Warning signs of cancer have been outlined by the American Cancer Society. General signs and symptoms of cancer may include unexplained weight loss, fever, fatigue, pain, and skin changes. Signs and symptoms of specifi c types of cancer can include changes in bowel habits or bladder bleeding or discharge, thickening or lump in the breast or other body part, indigestion or diffi culty swallowing, a recent change in a wart or mole, other skin changes, or a nagging cough or hoarseness. 2. Guidelines for screening asymptomatic people for the presence of cancer have been established by the American Cancer Society, the National Cancer Institute, and the U.S. Preventive Health Services Task Force, among others. Because many cancers do not produce signs or symptoms until they have become large, the goal of screening is to detect cancers early, when the disease may be more likely to be curable, thus potentially reducing cancer-related mortality. Th e diff erent sets of guidelines vary slightly in their recommendations for age and frequency of screening procedures. 3. Tumor markers are biochemical indicators of the presence of neoplastic proliferation detected in serum, plasma, or other body fl uids. These tumor markers may be used initially as screening tests, to reveal further information aft er abnormal test results, or to monitor the effi cacy of therapy. Elevated levels of these markers are not defi nitive for the presence of cancer because levels can be elevated in other benign and malignant conditions, and false-positive results do occur. Examples of some commonly used markers include the following: a. Carcinoembryonic antigen (CEA) for colorectal cancer b. -Fetoprotein (AFP) for hepatocellular carcinoma or hepatoblastoma c. Prostate-specifi c antigen (PSA) for prostate cancer 4. Tumor biopsy. The defi nitive test for the presence of cancerous cells is a biopsy and pathological examination of the biopsy specimen. Several types of procedures are used in the pathological analysis of tumors, including evaluating the morphological features of the tissue and cells (via pathologic evaluation), looking for cell-surface markers (via fl ow cytometry), and cytogenetic evaluation for specifi c chromosomal abnormalities (via fl uorescence in situ hybridization). 5. Imaging studies, such as radiograph, CT scans, MRI, and positron emission tomography (PET), may be used to aid in the diagnosis or location of a tumor and to monitor response to treatment. 6. Other laboratory tests commonly used for cancer diagnosis include complete blood counts (CBCs) and blood chemistries. A CBC measures the levels of the three basic blood cells—white cells, red cells, and platelets. a. The CBC will oft en include an absolute neutrophil count (ANC), which measures the absolute number of neutrophils in a person’s white blood count. Th e ANC is calculated by multiplying the white blood count (WBC) ( total neutrophils (segmented neutrophils percent ) segmented bands percent) ANC. Segmented neutrophils are oft en listed as “polys” and segmented bands are immature “polys.” II. CELL LIFE CYCLE is essential to the understanding of the activity of chemotherapy agents in the treatment of cancer A. Phases of the cell cycle 1. M phase, or mitosis, is the phase in which the cell divides into two daughter cells. 2. G1 phase, or postmitotic gap, is when RNA and the proteins required for the specialized functions of the cell are synthesized in preparation for DNA synthesis. 3. S phase is the phase in which DNA synthesis and replication occurs. 4. G2 phase, or the premitotic or postsynthetic gap, is the phase in which RNA and the enzymes topoisomerase I and II are produced