Chapter 2 Pharmacodynamics Objectives 1.know the different types of adverse reactions 2.Understand the pharmacological terms in this chapters (agonist , antagonist, side reaction, potency et al) 3. Understand the meaning of parameters such as Emax, ED50, TI et al. 4. Know how to analyse the D-R curve. 2 Pharmacodynamics deals with the study of the biochemical and physiological effects of drugs and their mechanisms of action. 3 Section 1 Basic Effects of Drugs Chapter 2 4 Principles of Drug Action Drugs do not produce new function, only modify existing functions. Actions can be considered therapeutic in one case and adverse in another Drug has both therapeutic and adverse reactions 5 Ⅰ、 Drug Action & Pharmacological Effect Drug Action: initial actions, how the drug works Pharmacological Effect: consequence of drug action on body Example: Aspirin action block prostaglandin synthesis effect analgesia & antipyresis 6 Ⅱ、Therapeutic Effects and Adverse Reactions Etiological treatment Therapeutic Symptomatic treatment Effect Supplement therapy Effect of Drug Side effect Toxic reaction Adverse Reactions Residual effect Withdrawal reaction Allergic reaction Idiosyncrasy Addiction 7 Ⅲ、Adverse Drug Reaction (ADR) Effects that are not desired. Most ADR is the intrinsic effects of drugs. It can be foreseen in common, but not always be avoided. Drug-induced disease: the unintended effect of a drug that results in mortality or morbidity with symptoms sufficient to prompt a patient to seek medical attention and/or to require hospitalization. 8 1. Side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended. 1. Pharmacological effects 2. Therapeutic dose 3. Low selectivity 4. Mild and recoverable 9 salivary secretion Atropine Macetylcholine R blocker Inhibition of sphincter pupilla Dry mouth pupil dilation Relieve the cardiac inhibition by vagus nerve Heart rate gastrointestinal relaxation spasmolysis 10 2. Toxic Reaction, Toxicity 1. Dosage or blood concentration is above therapeutic level 2. Extention of Pharmacological effects 3. Severe pathological changes/damage 11 Acute toxicity: – Mostly damage to the function of circulatory, respiratory and nervous system Digoxin Bleomycin Diazepam Amphetamine /Methamphetamine/ “Ice” 12 Chronic toxicity – Mostly damage to the function of liver, kidney, bone marrow and endocrine secretion Antihyperlipidemic Furosemide Chloramphenicol Glucocorticoids 13 Teratogenesis Carcinogenesis Mutagenesis phocomelia by thalidomide Deafness by aminoglycoside(gentamycin) is related to the DNA mutation of mitochondria in the cochlear hair cell 14 3. After Effect (Residual Effect) The residual effect: after withdrawal of the drug whose concentration is below the threshold Barbiturates hypnotic hangover next morning 15 4. Withdrawal Reaction Original disease aggravates after sudden drug withdrawal—— Rebound Reaction Glucocorticoids 16 5. Allergy (Hypersensitive Reaction) D + Protein (half-antigen) DP (antigen) 1. Not related to pharmacological effects 2. Degree is not related to dose Different drugs, Same reaction 17 6. Idiosyncrasy Unusual and unexpected sensitivity exhibited by an individual to a particular drug or food 1. Genetic variation 2. Consistent to the pharmacological effect 3. Degree : parallel to the dose ? 18 Glucose 6 phosphate dehydrogenase(G6PD) deficiency acute hemolysis after taking medicine of Quinine/broad bean (favism ) . Halothane malignant hyperthermia: hyperthermia, hypertension, tachycardia, muscle rigidity, and metabolic acidosis 19 7. Addiction 1. A state of dependence produced by the habitual taking of an certain drug 2. Physical dependence : narcotic drugs opioids, cocaine, mariguana 3. Psychological dependence: barbiturates 20 药物即毒物,利弊并存, 必须权衡,正确应用 21 Targets of drugs Receptors Enzymes Ion channels: Ca2+ K+, Na+, Cl- Transporters Immune system Genes: gene therapy , gene engineering drug Others 22 Chapter 2 Section 2 Interaction between Drug & Receptor Pharmacodynamics relates to drugs binding to receptors and their effects. 23 1. Definition of Receptor Endogenous ligand Drug Receptor A kind of functional protein which mediates signal transduction of cell. Signal amplification system Physiological & Pharmacological Effects 24 Definitions Agonist: a drug is called an agonist when binding to the receptor results in a response Antagonist: a drug is called an antagonist when binding to the receptor do not produce a response. It ocupy the receptor and block the agonist’s action 25 Competitive antagonist – shifts agonist curve to the right – characteristics • The maximum response is not depressed • blocks active site and can be overcome by ↑ agonist 26 Noncompetitive antagonist – shifts agonist curve downward – characteristics • does not block active site, therefore no ↑ antagonist can overcome effect • Maximum effect is reduced 27 28 • • Definitions Affinity: ability of drug to bind to receptor, i.e. how well a drug and a receptor recognize each other. Potency: amount of a drug that is needed to produce a given effect. EC50 is concentration or dose of drug that causes 50% of maximum effect – potency is determined by affinity of drug for receptor and number of receptors available. Efficacy: maximum effect that a drug can produce, regardless of dose. 29 Dose-effect curve X axis Dose: rectangular hyperbola LogD: “S” shape 30 Plots of dose (or log dose) versus response form D-R curve D-R curve can reveal information about affinity, potency, and efficacy of these agonists. 31 Affinity can be compared only when two drugs bind to the same receptor, the nearer to the Y-axis, the greater the affinity (A:B; X:Y? ) In term of potency, A > B; X > Y; In term of efficacy, A= B; X > Y 32 100% Responses increase in ● Drug effect direct proportion to dose Response increment diminishes finally when dose reaches at Emax maximum effect EC50: 50% 0 concentration of drug that produces 50% of maximal effect ● logD 33 Pre-test for USMLE Drug affinity for a receptor is most closely associated with its: A. potency B. efficacy C. selectivity D. toxicity E. safety A 34 Relation between receptor binding & effect: D+R DR E [D][R] At equilibrium , KD = DR (KD : the equilibrium dissociation constant) [RT] = [R] + [DR], So: DR RT D = KD + D Relative R-binding([DR] / RT) determines the relative effect (E/Emax) 35 E [ DR ] [ D] Emax [ RT ] K D [ D ] [D] = 0 E= 0 [D] >> KD DR / RT = 100%, Maximal efficacy DR / RT = 50% E= 50%Emax (EC50), KD=[D] KD is the [D] when the E reach half of Emax, means that a drug occupy 50% of the receptors present. 36 Parameters KD & affinity: – KD is inversely proportional to affinity KD = [D] EC50 pD2 = -logKD, is proportional to Affinity 37 Emax & intrinsic activity (α,the property of a drug that determines the amount of biological effect produced per unit of drug-receptor complex formed. ) – 100% 0 – Emax represents the efficacy of drugs – Emax reflects the intrinsic activity of drugs 38 Full agonists : produce the maximal response, α=1; Partial agonists : are incapable of eliciting a maximal response, less effective than full agonists;α<1 eg: Pentazocine 39 Duality of Partial Agonists The lower curve represents effects of a partial agonist when used alone, its ceiling effect = 50% of maximal in this example As the partial agonist displaces the full agonist from the receptor, the response is reduced, the partial agonist is acting as an antagonist 40 Antagonistic Index (pA2) The negative logarithm to the base 10 of the molar concentration of antagonist that makes it necessary to double the concentration of agonist needed to elicit the original submaximal responsein the absence of antagonist (Schild, 1947, 1949). pA2 log K A pA2 indicates the potency of antagonist,the greater of pA2,the more potent of antagonism 41 Therapeutic toxic Therapeutic index (TI): LD50/ ED50 Median effective dose Median lethal dose 42 Safety range : the distance between ED95 and LD5. Therapeutic Window : the concentration range of drug producing therapeutic effect. 43 Examples of narrow therapeutic index drugs •Warfarin •Lithium •Digoxin •Phenytoin •Gentamycin •Amphotericin B •5-fluorouracil •AZT (zidovudine) 44 Category of Receptor G protein-coupled receptors Ligand-gated ion channel receptors Tyrosine-kinase receptors Intracellular receptors – receptors in cytoplasm: steroid hormone – receptors in nucleus: thyroxine Other receptors 45 Receptor Regulation Receptor desensitization: – Agonist-specific desensitization: • phosphorylation or shift inward of receptor – Agonist-nonspecific desensitization: Receptor hypersensitization: – withdrawal reaction down-regulation & up-regulation – kinds of de- and hypersensitization when only involving change of the density of receptor. 46 Which statement is correct according to the above figure? a. Drug A is most efficacious because its ED50 is lowest. b. Drug B is the least potent drug among the three drugs shown. c. Drug C is the most potent drug. d. Drug B is more potent than drug C, and more efficacious the drug A. 47