UOFCM Pharmacology Lecture Notes 2024-2025 - PDF

UOFCM 2024-2025 1st trimester Pharmacology course Lec 3  Lec 3 Pharmacodynamics Pharmacodynamics Describes the actions of a drug on the body. Most drugs exert effects, both beneficial and harmful, by interacting with specialized target macromolecul...

UOFCM 2024-2025 1st trimester Pharmacology course Lec 3  Lec 3 Pharmacodynamics Pharmacodynamics Describes the actions of a drug on the body. Most drugs exert effects, both beneficial and harmful, by interacting with specialized target macromolecules called receptors, which are present on or in the cell. The drug-receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction. Fundamentals of drug action 1. Activation By binding to the target site if the drug molecule stimulates the process or selectively accelerates the process. For example, caffeine causes CNS stimulation and increased alertness. 2. Inhibition On the target site a drug molecule exhibiting its action by inhibiting the process or selectively deaccelerating the process. For example, aspirin inhibits cyclooxygenase, thereby inhibiting the formation of prostaglandins. Fundamentals of drug action 3. Complexation On the target site, the drug molecule exhibiting its action by making a complex, thereby making it inactive by sequestration. For example, deferoxamine chelates ion 4. Neutralization The drug molecule binding to the target site and neutralizing the action of the existing molecule directly through a chemical reaction [for example, antacids (sodium bicarbonate, magnesium hydroxide)] or physical interaction (polyvalent anti-snake venom). SIGNAL TRANSDUCTION Drugs act as signals, and receptors act as signal detectors. A drug is termed an "agonist" if it binds to a site on a receptor protein and activates it to initiate a series of reactions that ultimately result in a specific intracellular response. “Second messenger” or effector molecules are part of the cascade of events that translates agonist binding into a cellular response SIGNAL TRANSDUCTION Major receptor families Transmembrane Transmembrane G protein– ligand-gated coupled ion channels receptors Intracellular Enzyme-linked receptors receptors: SIGNAL TRANSDUCTION Major receptor families 1- Transmembrane ligand-gated ion channels The channel is usually closed until the receptor is activated by an agonist, which opens the channel for a few milliseconds e.g. Cholinergic nicotinic receptor is stimulated by acetylcholine opens a channel that allows sodium influx and potassium outflux across the cell membranes of neurons or muscle cells. SIGNAL TRANSDUCTION Major receptor families 2. Transmembrane G protein–coupled receptors The extracellular portion of this receptor contains the ligand-binding site, and the intracellular portion interacts (when activated) with a G protein These responses usually last several seconds to minutes. Often, the activated effectors produce “second messenger "molecules that further activate other effectors in the cell, causing a signal cascade effect.. E.g. α and β adrenoceptors SIGNAL TRANSDUCTION Major receptor families 3-Enzyme-linked receptors: This family of receptors undergoes conformational changes when activated by a ligand, resulting in increased intracellular enzyme activity E.g. growth factors and insulin receptors possess tyrosine kinase activity. When activated, the receptor phosphorylates tyrosine residues on itself and other specific proteins. SIGNAL TRANSDUCTION Major receptor families 4. Intracellular receptors: The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular, and, therefore, the ligand (for example, steroid hormones)must have sufficient lipid solubility to diffuse into the cell to interact with the receptor Signaling mechanisms for drug effect Five major signaling mechanisms are recognized: 1- Trans membrane diffusion of drug to bind to an intracellular receptor. 2- Trans membrane enzyme receptor, whose outer domain provides the receptor function and inner domain provides the effector mechanism. 3-Transmembrane receptors that, after activation by an appropriate ligand, activate separate mobile protein tyrosine kinase molecules (Janus Kinases or JAKs), which phosphorylate (signal transducer and activators of transcription or STAT) molecules that regulate transcription. Signaling mechanisms for drug effect Five major signaling mechanisms are recognized: 4- Trans membrane channels that are gated open or closed by the binding of a drug to the receptor site. 5- G-Protein coupled receptors, which utilize a coupling protein to activate a separate effector molecule.  Response of Drug-Receptor Interaction If a drug has affinity for the receptor, and if it is in close proximity of the receptor site, receptor-occupancy take place. This drug- receptor coupling leads to a variety of responses depending upon the nature of drug molecule: 1- Agonist: 2-Antagonists 3- Partial agonists: 4- Inverse agonists:  Response of Drug-Receptor Interaction 1- Agonist: Drug that resemble the natural transmitter or hormone, may activate the concerned receptor and result in response, so an agonist has “affinity” as well as “intrinsic activity” (( Capacity of drug to interact with a receptor )) = affinity. (( Capability to produce a response )) = intrinsic activity e.g. : Nor adrenaline, Acetyl choline, and their chemical analogues  Response of Drug-Receptor Interaction 2-Antagonists: Drugs have affinity to receptors without intrinsic activity. e.g. antiadrenergic 3- Partial agonists: Drugs have affinity but very low intrinsic activity 4- Inverse agonists: Drugs produce actions specifically opposite to these of agonist. e.g. B-carbolines.  Combined use of drugs 1- Synergism 2- Antagonism: a) Additive: This occur when two drugs Drug antagonism results reduced have similar action and these are biological activity. E.g. naloxone additive action and opioid drugs. b) Potentiation : This occurs when one drug increases the action of another. It is either due to the two drugs acting by different mechanisms, or one delays excretion or metabolism of the other.   Therapeutic Index (Safety Margin) In human, range of effective doses (up to ED max) and range of toxic doses (from minimal toxic dose upward) are determined. These two dosage ranges may be widely apart indicating wide margin of safety(( High therapeutic index)), or may be close indicating low margin of safety ((Low therapeutic index )).  Therapeutic Index (Safety Margin)  Therapeutic Index (Safety Margin)  Therapeutic Index (Safety Margin)  Mechanism of drug action 1- On cell membrane : (a)Action of receptors of agonists and antagonist. (b) Action on enzymes and pumps. (c) Action on ion channels. (d) Physico-chemical interaction 2- On intracellular constituents: (a) Cytosolic or nuclear receptors. (b) Enzymes: MAO, ChE or Xanthine oxidase. (c) DNA or RNA, e.g. the use of different anticancer drugs. (d) Transport carrier molecules, e.g. probenacid on renal tubules. 3- Outside the cell (a) Chemical interaction, e.g. chelating agents, antacids. (b) Physical mechanisms, e.g. osmotic diuretics, osmotic purgatives. 4- Antimicrobial action  Structure activity and Receptor classes 1- Structure-activity relationship: The same receptor type may mediate two effects (e.g. Cardio stimulation and broncho-relaxation), a competitive antagonist (e.g. Propranolol) will inhibit both responses of the agonist adrenaline 2- Strereoselectivity: Drug molecule have more than one 3- dimensional configuration, biological activity for each is different. 3- Receptor classes: There are multiple receptor subtypes for each endogenous ligands, e.g. Ach(5), NA(5), H(3), 5-HT(4).  Quantitative variation in drug response Response to drugs vary from animal to animal, Human to human because of normal biological variation, response may changed quantitatively in the same individual during the course of therapy 1- Up and down regulation of receptors 2- desensitization and tachyphylaxis 3- Tolerance: 4- Drug resistance;  Quantitative variation in drug response 1- Up and down regulation of receptors Upregulation (i.e., increase in the number) of receptors occurs when the activity of the receptor is lower than usual (e.g., due to long-term administration of an antagonist). For example, administration of beta-blockers upregulates β-adrenoreceptors  Quantitative variation in drug response 2- desensitization and tachyphylaxis a- Change in receptors b- loss of receptors. c- Exhaustion of mediators.  Quantitative variation in drug response 3- Tolerance: A gradual decrease in responsiveness (in vivo) to a drug, taking days or weeks to develop. It requires either raising the dose or substituting a different drug (a) Pharmacokinetic tolerance. (b) Pharmacodynamic tolerance. I- Physiological adaptation. ii- Tissue tolerance. (c) Cross tolerance. (d) Pharmaco-genetic tolerance.  Quantitative variation in drug response 4- Drug resistance; the term used in the field of chemotherapy during antimicrobial therapy or chemotherapy of malignancy.  Adverse drug Reactions (Toxicity) Measurement of pre- clinical Toxicity: Before any new compound is approved for clinical use, extensive toxicity testing is done in various animal species. The major kinds of information needed from such study are: (i) Acute toxicity. (ii) Subacute and chronic toxicity-effects of multiple doses given for weeks or months. (iii) Effect on reproduction including teratogenicity. (iv) Carcinogenicity. (v) Mutagenicity.  Adverse drug Reactions (Toxicity) Definitions of commonly used terms Side effects: some reaction are due to excess of normal, predictable, dose related, Pharmacodynamics effects seen in therapeutic doses. (also called type A reaction)  Secondary effects: Super infection or vitamin deficiency during chemotherapy.  Intolerance: Low threshold to pharmacological action of a drug. An inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses  Adverse drug Reactions ADR (Toxicity) Definitions of commonly used terms Iatrogenic diseases: This is drug-induced diseases such as: (i) Parkinson’s syndrome during therapy with phenothiazine. (ii) Gastric ulcer with NSAIDs. (iii) Candidiasis with broad spectrum antibacterials. (iv) Glaucoma with ocular corticosteroids  Adverse drug Reactions ADR (Toxicity) Factors Influencing ADR 1- Drugs. 2- Patients : a- age b- sex c- pregnancy. 3- Diseases : a- hepatic dysfunction b- renal dysfunction ……etc. 4- Genetic factors.  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the Maximum effect) Two important drug characteristics, potency and efficacy, can be determined by graded dose–response curves.  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations Potency: Potency is a measure of the amount of drug necessary to produce an effect. The concentration of drug producing 50% of the maximum effect (EC50)  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations Efficacy: Efficacy is the magnitude of response a drug causes when it interacts with a receptor. Efficacy is dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug (its ability to activate the receptor and cause a cellular response). Maximal efficacy of a drug (Emax) assumes that the drug occupies all receptors, and no increase in response is observed in response to higher concentrations of drug.  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations The maximal response differs between full and partial agonists, even when the drug occupies 100% of the receptors. Similarly, even though an antagonist occupies 100% of the receptor sites, no receptor activation results and Emax is zero. Efficacy is a more clinically useful characteristic than potency, since a drug with greater efficacy is more therapeutically beneficial than one that is more potent  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations  DOSE–RESPONSE RELATIONSHIPS Graded dose–response relations Thank you