Pharmacodynamics - PDF

Pharmacodynamics Dr: Ahmed Atia Pharmacodynamics: The effect of drugs on biological systems What drugs do to the body (pharmacological effects) How drugs do it (mechanism of drug action)  Pharmacodynamics (how drugs work on the body) Ø...

Pharmacodynamics Dr: Ahmed Atia Pharmacodynamics: The effect of drugs on biological systems What drugs do to the body (pharmacological effects) How drugs do it (mechanism of drug action)  Pharmacodynamics (how drugs work on the body) Ø many drugs inhibit enzymes Enzymes control a number of metabolic processes A very common mode of action of many drugs Ø in the patient (ACE inhibitors) Ø in microbes (sulfas, penicillins) Ø some drugs bind to: Ø proteins (in patient, or microbes) Ø the genome (cyclophosphamide)  Pharmacodynamics Ø most drugs act (bind) on receptors Ø in or on cells Ø form tight bonds with the ligand Ø exacting requirements (size, shape) Ø can be agonists (salbutamol), or antagonists (propranolol) Ø receptors have signal transduction methods Drug Receptor A macromolecular component of a cell with which a drug interacts to produce a response Usually a protein  The Receptor and Binding Pre Synaptic cleft POST Affinity: It is the ability of the drug to combine or bind with the receptors. Intrinsic activity (Efficacy): It is the ability of the drug to activate the receptor following receptor binding. Affinity and intrinsic activity are independent, i.e. drugs with the same affinity can possess different degrees of intrinsic activity & vice versa.  High Affinity Binding High Affinity – the ligand binds well and remains bound long enough to activate the receptor. PRE Synaptic cleft POST  High Affinity Binding Low Affinity – the ligand binds less well and may not remain bound long enough to activate the receptor. PRE Synaptic cleft POST  High Affinity Binding High Intrinsic Activity – the ligand produces a large effect on the post synaptic cell. PRE Synaptic cleft POST  High Affinity Binding Low Intrinsic Activity – the ligand produces a small or inconsistent effect on the post synaptic cell. PRE Synaptic cleft POST  Agonists and antagonists Ø agonist has affinity plus intrinsic activity Ø antagonist has affinity but no intrinsic activity Ø partial agonist has affinity and less intrinsic activity Ø competitive antagonists competes with agonist for receptor  Agonist Drugs drugs that interact with and activate receptors; they possess both affinity and efficacy two types Full – an agonist with maximal efficacy Partial – an agonist with less then maximal efficacy Agonist High affinity High intrinsic activity Agonist  Agonist Dose Response Curves Full agonist Partial agonist Response Dose Antagonist Drug Antagonists interact with the receptor but do NOT change the receptor they have affinity but NO efficacy two types Competitive Noncompetitive Antagonist High affinity Low intrinsic activity Antagonist  Competitive Antagonist competes with agonist for receptor Antagonism can be overcome with increasing agonist concentration reduces the apparent affinity of the agonist. Competitive Antagonist Noncompetitive Antagonist Drug binds to receptor and stays bound Irreversible – does not let go of receptor This looks like competitive antagonist but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect Noncompetitive Antagonist Desensitization (down regulation) Ø agonists tend to desensitize receptors Ø homologous (decreased receptor number) Ø heterologous (decreased signal transduction) Ø antagonists tend to up regulate receptors  Signal transduction 1. enzyme linked (multiple actions) 2. ion channel linked (speedy) 3. G protein linked (amplifier) 4. nuclear (gene) linked (long lasting) Receptors serves 2 essential functions: Ø Recognition of the specific ligand molecule & Ø Transduction of the signal into a response. Accordingly, the receptor molecule has 2 sites: ü Ligand binding domain and ü Effector domain which undergoes a functional conformational change These domains have now actually been identified in some receptors. The binding in the receptor molecule is translated into the response.  Signaling or Transducer Mechanisms These mechanisms of translation of receptor activation leading to response can be grouped into 4 major groups. 1. G-protein coupled receptors 2. Receptors with ion channel 3. Enzymatic receptors 4. Receptors regulating gene expression  1. G-protein coupled receptors These are a large family of cell membrane receptors which are linked to the effector (enzyme / channel) through one or more G- proteins for generating a response.  It has seven membrane-spanning regions, and are linked to a G protein (Gs and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit The agonist binding site is located somewhere between the loops on the extracellular side, while another binding site is formed by cytosolic loops for G-protein. G-proteins float in the membrane with their exposed domain (site) lying in the cytosol.  Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α subunit. Dissociation of the G protein occurs, and both the α- GTP subunit and the βγ subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel. These effectors then change the concentrations of second messengers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes.  Second Messengers Second messengers are essential in conducting and amplifying signals coming from G protein–coupled receptors. A common pathway turned on by G proteins is the activation of adenylyl cyclase by α-GTP subunits, which results in the production of cyclic adenosine monophosphate (cAMP)—a second messenger that regulates protein phosphorylation. G proteins also activate phospholipase C (PLC), which is responsible for the generation of two other second messengers, namely inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well.  Second Messengers The first messenger promotes the cellular production or mobilization of a second messenger, which initiates cellular signaling through a specific biochemical pathway. cAMP; IP3; DAG; Ca++ The cAMP second messenger pathway  Ca++ - phosphoinositide signaling pathway. PIP2: Phosphatidylinositol 4,5-bisphosphate Inactive ( R ) Active (R + L) α β γ G-protein αα β γ GDP GTP α α E GTP GDP i) cAMP ii) IP3-DAG EA iii) Channel i) cAMP Pathway PKA phosphorylates & alters the function of many enzymes, ion channels, carriers & structural proteins to result in an increased contractility / impulse generation (heart), relaxation (smooth muscle), glycogenolysis, lipolysis, inhibition of secretion / mediator release, modulation of junctional transmission, hormones synthesis etc. ii) Phospholipase C: IP3- DAG Pathway R PIP2 GProtein PLc + CCPK DAG IP3 Pkc MLCK CAM Other Effectors Ca++ Ca++ Ø IP3 mobilizes Ca++ from intracellular depots Ø DAG enhances protein kinase C (PKc) activation by Ca++ Ø Ca++ is a highly active regulator acting through calmodulin, PKc, & other effectors to mediate / modulate contraction, secretion, transmitter release, neuronal excitability, intracellular movements, membrane function, metabolism, cell proliferation etc. iii) Channel regulation Ø The activated G-proteins can also open or close ionic channels specific for Ca++, K+, or Na+ and bring about hyperpolarization / depolarization / changes in intracellular Ca++. Ø Physiological responses like changes in inotropy, chronotropy, transmitter release, neuronal activity & smooth muscle relaxation follows.  2. Receptors with Ion Channels Ø Some receptors on the cell membrane enclose ion selective channels for Na+, K+, Ca++ or Cl- within their molecules. Ø Agonist binding opens the channel & causes depolarization / hyperpolarization / changes in cytosolic ionic concentration, depending on the ion that flows through. Ø Receptors that come in this category are: a) Nicotinic cholinergic b) GABA c) Glycine d) Aspartate e) Glutamate f) Serotonin (5-HT3)  § It’s a pentamer made up of 5 polypeptide subunits (2α, 1β, 1γ, & 1δ). § When Ach binds to sites on α subunits, a conformational change occurs that result in the opening of a central aqueous channel through which Na+ ions move from the extracellular fluid into the cell. Nicotinic Ach receptor, a ligand-gated ion channel v The onset & offset of responses through this class of receptors is the fastest as the agonists operate these channels without involvement of any coupling protein or second messenger.  3. Enzymatic Receptors Polypeptides with 2 domaines: 1. Extracellular hormone binding domain 2. Cytoplasmic enzyme domain [protein tyrosine kinase / serine kinase / guanylyl cyclase] Examples: Insulin Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF) Atrial natriuretic peptide (ANP) etc. Ligand binds to receptor’s extracellular domain – resulting change in receptor conformation – causes receptor molecules to bind to one another – brings together tyrosine kinase domains which become enzymatically active & phosphorylates one another as well as additional downstream signaling proteins – thereby allowing a single type of activated receptor to modulate a no. of biochemical processes.  Ø For example Insulin uses a single type of receptors to trigger ↑uptake of glucose & amino acids and to regulate metabolism of glycogen & triglycerides in the cell. Epidermal growth factor (EGF) receptor Ø The receptor has extracellular & cytoplasmic domains above & below the plasma membrane Ø Receptor converts from inactive to active state on binding with EGF. Ø Cytoplasmic domains become phosphorylated on specific tyrosine residues (Y) & their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins (S).  4. Intracellular Receptors Ø Ligands that cross cell membrane & act on the intracellular receptors are lipid soluble. Ø Two types: Cytoplasmic or Nuclear Ø Example: Corticosteroids Mineralocorticids Sex steroids Vit. D Thyroid hormone Ø Stimulate transcription of genes in nucleus by binding to specific DNA sequence near the gene whose expression is to be regulated End show Thanks