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MODULE 4 PHARMACOLOGY &PHARMACOKINETICS TOXICOLOGY INCOMPATIBILITIES & ADVERSEDRUG REACTIONPHARMACOLOGYPharmacology  Study of selective biologic activity of drugs  Study of substances that interact w/ living systems through chemical processes, especially by binding to regulatory...

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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.  Articles recognized in the official USP, official Homeopathic Pharmacopeia of the US or the official NF, or any supplements to any of them Drugs  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) M1-Gq 1- Gq B2  bronchodilation (lungs) M2-Gi 2- Gi Gi  inhibit adenylyl cyclase; decreases cAMP M3-Gq 1-Gs Alpha-2, 5-HT1A , muscarinic, histamine receptors 2-Gs Go  unknown 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 Processes: L Pharmacokinetics  The actions of the body on the drug, A including absorption, distribution, metabolism, and D elimination. M Elimination of a drug may be achieved by metabolism or by E R excretion. Transport Processes: Transport  mechanism of the drug which it moves across the cell membrane. 1. Passive Diffusion      

 Liberation  Absorption  Distribution  Metabolism  Excretion  Response

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 & ...