Pharmacodynamics PDF

Pharmacodynamics Maryam Sawalha 1  Important definitions in Pharmacodynamics: Action: How and where the effect of drug is produced Effect: the type of response producing by drug 3  Potency: the amount of d...

Pharmacodynamics Maryam Sawalha 1  Important definitions in Pharmacodynamics: Action: How and where the effect of drug is produced Effect: the type of response producing by drug 3  Potency: the amount of drug necessary to produce an effect of a given magnitude.  Refers to the concentration (EC50) or dose (ED50) required to produce 50% of the drug's maximal effect Efficacy (Magnitude of effect): maximal response  references the response to the drug  Mechanism of drug action Majority of drugs interact with target biomolecule (usually proteins) Enzymes Ion channels Neurotransmitter transport systems Nucleic acids Receptors 6  Receptor mediated action Drugs produce their effects through interacting with some chemical compartment of living organism (receptor). Receptors are macromolecules Most are proteins Present either on the cell surface, cytoplasm, or in the nucleus Receptors: A macromolecular component of a cell with which a drug interacts to produce a response Drug-Receptor Interactions Drug/Receptor Binding Mimic actions of neurotransmitter at same site (agonist) (as endogenous molecules) Bind to nearby site and facilitate neurotransmitter binding (agonist) Block actions of neurotransmitter at same site (antagonist) Types of Receptors: 1. Membrane receptors 1.Ion channels (Ligand-gated Ion Channels) 2.G-protein coupled receptors 3.Enzyme-linked receptors 2.Intracellular receptor 9 Membrane Receptor Classes Figure 6-5: Four classes of membrane receptors  1. Ligand-gated Ion Channels The activity is regulated by the binding of a ligand to the channel. Response to these receptors is: very rapid Lasts only a few milliseconds. Mediate diverse function Neurotransmission Cardiac or skeletal muscle contraction 12 Ligand Gated Ion Channel  2. G-protein coupled receptors Seven transmembrane domains Extracellular ligand-binding site Intracellularly Linked to a G proteins (Gs, Gi, and others) Having three subunits, α subunit that binds GTP,β and Y Response usually lasts several seconds to minutes 14  G-Protein-coupled Receptors Figure 6-11: The G protein-coupled adenylyl cyclase-cAMP system  3. Enzyme-linked receptors: This types of receptors form dimers or multisubunits Activation increases cytoplasmic enzyme activity e.g., tyrosine kinase The activated receptor phosphrylates tyrosine residues it self and then other speciic proteins Phosphorylation can modify the structure of the target protein Figure 6-10: Tyrosine kinase, an example of a receptor-enzyme 20  3. Enzyme-linked receptors: Responses last on the order of minutes to hours. Metabolism, growth, and differentiation are controlled by these types of receptors. The most common enzyme-linked receptors: Epidermal growth factor platelet-derived growth factor Atrial natriuretic peptide Insulin These receptors have a tyrosine kinase activity as part of their structure. 21 22 24  Drug-receptor binding Covalent bonds: 1. Drug and receptor share a pair of electrons 2. Very strong bond 3. Not very common in drug pharmacology Electrostatic bonds: 1. Attraction due to charge differences 2. Vary in strength Very strong (ionic bonds) Very weak (van der Waals forces) 3. Most common in pharmacology 26  Drug-receptor binding D + R DR Complex Affinity Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor  Covalent bonds are stable and essentially irreversible Electrostatic bonds may be strong or weak, but are usually reversible 27  Drug Receptor Interaction DR Complex Effect Efficacy: (or Intrinsic Activity) – ability of a bound drug to produces an effect  Pharmacodynamics: Major roles of receptors Drugs typically exert their effects by interacting with a receptor Drug-receptor interactions have been important in: New drug development Therapeutic decisions  Dose response curves Graded dose-response curve:(A response to a drug) such that as the dose of drug increases the intensity of the response increases. A graded dose- response relationship can be measured on a continuous scale Quantal dose-response curve: can be constructed for drugs that elicit an all-or-none response (there either is or is not a response), eg, presence or absence of epileptic seizures  Graded dose–response Relations Potency: the amount of drug necessary to produce an effect of a given magnitude. Refers to the concentration (EC50) or dose (ED50) required to produce 50% of the drug's maximal effect  Efficacy (Magnitude of effect): maximal response  references the response to the drug Therefore clinical effectiveness will depend not on potency but on maximal efficacy 32 From Nies A and Speilberg SP. Principles of Therapeutics. in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th edition, 1996. Pages 43-62.McGraw Hill, 37  Concepts to remember! Threshold: Dose that produces a just-noticeable effect. ED50: Dose that produces a 50% of maximal response. EC50: Concentration of the drug that produce 50%of maximal response Ceiling: Lowest dose that produces a maximal effect. 38  Dose-response curve 100 Ceiling 80 60 ED50 Response 40 20 Threshold 0 0.1 1 10 100 1000 10000 Log Dose 39  Onset: The time it takes for the drug to elicit a therapeutic response. Peak: The time it takes for a drug to reach its maximum therapeutic response. Duration: The time a drug concentration is sufficient to elicit a therapeutic response 42 Classification of a drug based on drug-receptor interactions 43  Agonist Drugs Two types:  Full agonist  Drug binds to a receptor and produces a maximal biologic response (efficacy) that mimics the response to the endogenous ligand  Partial agonist  Drug, no matter how high the dose, cannot produce a full response  Efficacy (intrinsic activity) greater than zero but less than full agonist  Have both agonist and antagonist properties.  Agonist Dose Response Curves Full agonist Partial agonist Response Dose  PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ. Full Agonist 1.0 Partial agonist % Maximal Effect 0.8 0.6 Partial agonist 0.4 0.2 0.0 0.01 0.10 1.00 10.00 100.00 1000.00 [D] (concentration units)  Antagonist Drug Drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response Two types: Competitive: Antagonist binds to samesite as agonist in a reversible manner. Noncompetitive: Antagonist binds tothe same site as agonist irreversibly.  Effectiveness, toxicity, lethality ED50 - Median Effective Dose 50 ; the dose at which 50% of the population or sample manifests a given effect. TD50 - Median Toxic Dose 50 - dose at which 50% of the population manifests a given toxic effect LD50 - Median Toxic Dose 50 - dose which kills 50% of the subjects Therapeutic Index = TD50 or LD50/ ED50 50 51 52  Unusual Responses: Definitions:  Idiosyncratic response: unusual response  Hyporeactive: less than normal response  Hyperreactive: more than normal response  Hypersensitivity: allergic or other immunological reaction  Tolerance: decreased response with continued administration  Tachyphylaxis: rapidly developing tolerance Pharmacokinetics  Absorption Definition : …The process by which a drug moves from its site of administration to the systemic circulation Most common route of administration is oral Also, Intramuscular, intradermal, subcutaneous, rectal, inhalation, topical etc.  Oral Absorption : GI epithelium is the main barrier. Adapted for absorption due to a large surface area. Most important mechanism is Passive diffusion  Factors That Affect Absorption Route of Administration of the drug Dosage formulation Status of the absorptive surface Rate of blood flow to site of administration PH at site of administration Status of GI motility Food or fluids administered with the drug Drug Absorption of Various oral dosage forms Gastric Emptying and Motility  Factors Affecting Gastric Emptying :  Distribution : The REVERSIBLE transfer of a drug between the systemic circulation and the tissues Refers to movement of drug into tissue (Usually a passive process). The transport of a drug in the body by the bloodstream to its site of action  Volume of distribution (VD, also known as apparent volume of distribution): is the theoretical volume It is defined as the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing.  Distribution Depends on: Areas of rapid distribution: heart, liver, kidneys, brain Areas of slow distribution: muscle, skin, fat Protein-binding Water soluble vs. fat soluble Blood-brain barrier  Distribution Plasma Protein Binding D+P ↔ DP Albumin (acidic drugs) Glycoprotein (basic drugs) Fibrinogen, lipoproteins (both, minor) Pharmacokinetics:Metabolism (Also Known As Biotransformation) The biologic transformation of a drug into an inactive metabolite, a more soluble compound, or a more potent metabolite. Liver (main organ). Kidneys. Lungs. Plasma. Intestinal mucosa.  Metabolic reactions Biotransformation is divided into two stages: Phase I biotransformation usually results in only a small increase in hydrophilicity. Typically introduces functional groups for subsequent conjugation in Phase II. Phase II biotransformation usually results in a large increase hydrophilicity, frequently follows phase I biotransformation. Metabolic reactions There are four main patterns of drug metabolism. These are: Phase I oxidation reduction Hydrolysis Phase II conjugation Cytochrome P450 (CYP) Biotransformations Chemically diverse small molecules are converted, generally to more polar compounds Reactions include: Aliphatic hydroxylation, aromatic hydroxylation Dealkylation (N-,O-, S-) N-oxidation, S-oxidation Deamination Dehalogenation Cytochrome P450 Isoforms CYP1A2 CYP3A4 CYP2C9 CYP2C19 CYP2D6 Cytochrome P450 Nomenclature, e.g. for CYP2D6 CYP = cytochrome P450 2 = genetic family D = genetic sub-family 6 = specific gene NOTE that this nomenclature is genetically based: it has NO functional implication Conjugation (Phase 2 Reactions) Major Conjugation Reactions Glucuronidation (high capacity) Sulfation (low capacity) Acetylation (variable capacity) Examples: Procainamide, Isoniazid Other Conjugation Reactions: O-Methylation, S-Methylation, Amino Acid Conjugation (glycine, taurine, glutathione) Conjugation reactions 1. Glucuronic acid conjugation 2. Sulfate conjugation 3. Glutathione conjugation (mercapturic acid) 4. Conjugation with amino acids (glycine, glutamine) 5. Acylation 6. Phosphorylation 7. Methylation (O, N, S)  Metabolism Factors that decrease metabolism: Cardiovascular dysfunction Renal insufficiency Starvation Obstructive jaundice Slow metabolizers: CYP or acetylators Metabolic Inhibition Some drugs can inhibit the metabolism of other drugs. Drug metabolism being an enzymatic process can be subjected to competitive inhibition. Example, warfarin inhibits tolbutamide elimination which can lead to the accumulation of drug and may require a downward adjustment of dose. Erythromycin or ketoconazole drug therapy. Cimetidine.  Metabolism Induction Some drugs can cause an increase over time in liver enzyme activity. This in turn can increase the metabolic rate of the same or other drugs. Example: Rifampin or Phenobarbitone will induce the metabolism of itself and other drugs. Cigarette smoking can cause increased elimination of theophylline and other compounds. Dosing rates may need to be increased to maintain effective plasma concentrations. Pharmacokinetics: Metabolism Delayed drug metabolism results in: Accumulation of drugs Prolonged action of the drugs Stimulating drug metabolism causes: Diminished pharmacologic effects  Pharmacokinetics: Excretion The elimination of drugs from the body Kidneys (main organ) Liver Bowel Biliary excretion Enterohepatic circulation Exhalation sweat, milk, semen….. Pharmacokinetic Parameters  Pharmacokinetic Parameters Clearance Apparent Volume of Distribution Half Life Area Under the Curve AREA UNDER THE CURVEAUC The AUC is a measure for the amount of drug that reached the systemic circulation. AUC  Half Life (t1/2) Is the time that it takes for the concentration C to drop to half of its initial value. t1/2 A measure of the rate at which drugs are removed from the body. Bioavailability F  AUC oral AUC iv Quantify absorption F is the fraction of the administered dose that reaches the systemic circulation (F = 0-1). MARYAM SAWALHA