Pharmacodynamics PDF

Dr Dante Estandarte PHARMACODYNAMICS  INTRODUCTION PHARMACODYNAMICS effects of drugs , mechanisms of action Effects differ from patient to patient PHARMACOGENETICS  “Corpora non agunt nisi fixata” A drug will not work unless it is bound (to a receptor)...

Dr Dante Estandarte PHARMACODYNAMICS  INTRODUCTION PHARMACODYNAMICS effects of drugs , mechanisms of action Effects differ from patient to patient PHARMACOGENETICS  “Corpora non agunt nisi fixata” A drug will not work unless it is bound (to a receptor) Receptor Occupancy Theory Assumes that response emanates from a receptor occupied by a drug Drugs commonly alter the rate or magnitude of an intrinsic cellular response rather than create new responses  Drug Target or Drug Receptor Protein molecules whose function is to recognize and respond to endogenous chemical signals = ligands Cellular macromolecule with which the drug interacts to elicit cellular response Usually located on the surface of cells; may be located in intracellular components such as the nucleus REGULATORY PROTEINS Types Physiological Receptors Sensing elements For endogenous chemical messengers e.g., hormones, neurotransmitters Also used by drugs as target molecules  Chemical bonds Covalent bonds – strong; usually irreversible binding Ionic bond – weak; between a cation and an anion Other weak electrostatic bonds – hydrogen, van der Waals, hydrophobic bonds Effect can be agonism or antagonism Agonism - initiating the same reaction or activity typically produced by the binding of an endogenous substance  Enzymes Drug molecule is a substrate analogue Drug as Competitive inhibitor False substrate resulting to formation of abnormal product that subvert the normal metabolic pathway Prodrug, requiring enzymatic degradation to convert to an active form Carriers or Transporters Usually involves hydrolysis of ATP > active transport of substance against electrochemical gradient  Ion Channels Gateways that selectively allow passage of particular ions, induced either to open or close Ion Selectivity - cation-selective or anion- selective Gating Ligand-gated channels – binding of agonist molecule Voltage-gated channel – change in transmembrane potential e.g., depolarization Ways by which drugs can affect ion channel function Altering the level of expression of ion channels on cell surface Binding to the channel protein itself Indirect interaction involving a G protein  TYPES OF RECEPTORS (ION CHANNELS) Type 1: Ligand-gated Ion Channels or Ionotropic Receptors Type 2: G protein-coupled Receptors Type 3: Kinase-Linked and Related Receptors Type 4: Nuclear Receptors  Coupling between receptor and ion channel is direct one Neurotransmitter acts on TYPE I: postsynaptic membrane (nerve or LIGAND- muscle) and transiently increases GATED ION its permeability to particular ions CHANNELS Control the fastest synaptic events OR in the nervous system IONOTROPIC RECEPTORS Ligand binding and channel opening occur on a millisecond timescale  Largest family Receptors for many hormones TYPE 2: G and slow neurotransmitters PROTEIN- G proteins comprise a family of COUPLED membrane-resident proteins whose function is to recognize RECEPTORS activated GPCRs and pass on (GPCRS) the message to the effector systems that generate a cellular response  Targets for G Proteins Adenyl cyclase, the enzyme responsible for cAMP formation cAMP regulates energy metabolism, cell division, cell differentiation, ion transport, ion channels, contractile proteins in smooth muscle cAMP activates protein kinases which regulate the function of many different cellular proteins by controlling protein phosphorylation Phospholipase C, enzyme responsible for inositol phosphate and diacylglycerol (DAG) formation Ion channels, particularly calcium and potassium channels Rho A/Rho kinase, a system that regulates the activity of many signaling pathways controlling cell growth and proliferation, smooth muscle contraction, etc.  Comprise an extracellular ligand-binding domain linked TYPE 3: to an intracellular domain; in many cases, the intracellular KINASE- domain is enzymic in nature LINKED (with protein kinase or AND guanylyl cyclase activity) RELATED Involved mainly in events controlling cell growth and RECEPTORS differentiation, and act indirectly by regulating gene transcription Two important pathways Ras/Raf/mitogen-activated protein (MAP) kinase pathway, activated by protein mediators e.g., hormones Important in cell division, growth and differentiation Jak/Stat pathway activated by many cytokines Controls synthesis and release of many inflammatory mediators  Regulate and modify gene transcription Receptors for steroid hormones such as estrogen and the glucocorticoids were present in the cytoplasm of cells and TYPE 4: translocated into the NUCLEAR nucleus after binding RECEPTORS with their steroid partner NRs can directly interact with DNA. Regard them as ligand-activated transcription factors that transduce signals by modifying gene transcription.  RECEPTOR BINDING SITES The ORTHOSTERIC site is where the ligand(s) bind, aka the active site. All other sites ,by definition, are ALLOSTERIC (ALLOTOPIC). AGONIST - Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds PRIMARY AGONIST - If the drug binds to the same recognition site as the endogenous agonist ALLOSTERIC (ALLOTOPIC) AGONIST - bind to a different region on the receptor For most drugs, binding and activation are reversible If an inhibitor binds to the orthosteric site the inhibition will be competitive, if it binds to an allosteric site the inhibition will not be competitive.  AGONISM AND ANTAGONISM AGONISTS – drugs that initiate the same reaction or activity typically produced by the binding of an endogenous substance FULL AGONIST – full response PARTIAL AGONISTS - drugs that are only partly as effective as agonists regardless of the concentration employed ANTAGONISTS - inhibition of or interference with the action of one substance  AGONISM CONSTITUTIVE ACTIVATION OF RECEPTORS (TWO-STATE RECEPTOR MODEL) Receptor mutations occur – either spontaneously, in some disease states e.g., autoimmune, or experimentally created An appreciable level of activation (constitutive activation) may exist even when no ligand is present Inverse agonist - drugs that stabilize such receptors in an inactive conformation BIASED AGONISM (FUNCTIONAL SELECTIVITY) Receptors have different conformations that they can adopt, and may produce different functional effects by activating different signal transduction pathways Different agonists can exhibit bias for the generation of one response over another even although they are acting through the same receptor ALLOSTERIC MODULATION Receptor proteins possess many other (allosteric) binding sites. Allosteric modulators bind to sites on the receptor other than the agonist binding site (orthosteric) and can modify agonist activity by: Altering agonist affinity, Altering agonist efficacy, Orthosteric agonism, or Directly evoking a response themselves e.g., allosteric agonism  ANTAGONISM COMPETITIVE ANTAGONISM Drugs combine with the receptors but do not activate them, and block the effect of agonists on that receptor Types Reversible Agonist and competitive antagonist molecules do not stay bound to the receptor but binds and rebind continuously (binding is reversible). There is equilibrium between association and dissociation of molecules with receptors Agonist cannot evict a bound antagonist molecule. By increasing dose of agonist, agonist Occupies a proportion of the vacant receptors Reduces the rate of association of the antagonist molecules with receptors >> surmountable  Irreversible (Non-equilibrium; Insurmountable) Antagonist binds to the same site on the receptor as the agonist but dissociates very slowly, or not at all, from the receptors (e.g., covalent bonding), with the result that no change in the antagonist occupancy takes place when the agonist is applied MECHANISMS OF ANTAGONISM Competitive Antagonism (Syntropic Interaction) - competition with an agonist for the same site on the receptor Allosteric Antagonism - interaction with other sites on the receptor Binding to a site on the receptor distinct from that of the primary agonist Affinity of the receptor for the agonist is decreased by the antagonist Combination with the agonist (Chemical Antagonism) - two substances combine in solution; as a result, the effect of the active drug is lost E.g. use of chelating agents that bind to heavy metals  Functional (or Physiological) Antagonism - interaction of two drugs whose opposing actions in the body tend to cancel each other Pharmacokinetic antagonism - one drug affecting the absorption, metabolism or excretion of the other Interruption or Block of Receptor–Response Linkage Non-competitive antagonism describes the situation where the antagonist blocks at some point downstream from the agonist binding site on the receptor and interrupts the chain of events that leads to the production of a response by the agonist.  The ability of a drug molecule to activate the receptor is actually a graded rather than an all-or-nothing property. Full agonists) can produce a maximal response (the largest response that the tissue is capable of giving), whereas partial agonists can produce only a submaximal response.  AFFINITY Tendency of a drug to bind to the receptors Strength of the reversible interaction between a drug and its receptor DRUG The higher the affinity of the AFFINITY, drug for the receptor, the EFFICACY lower the concentration at which it produces a given AND level of occupancy SPECIFICITY When two or more drugs compete for the same receptors; each has the effect of reducing the apparent affinity for the other Measured by dissociation constant EFFICACY Ability of a drug to activate a receptor and generate a cellular response A drug with a lower efficacy at the same receptor may not elicit a full response at any dose A drug with high efficacy may be a full agonist, eliciting, at some concentration, a full response A drug with a low intrinsic efficacy will be a partial agonist A drug that binds to a receptor and exhibits zero efficacy is an antagonist SPECIFICITY The conformation of a ligand (a molecule that binds to a receptor) is complementary to the space defined by receptor’s active site Specificity is reciprocal - individual classes of drug bind only to certain targets; and individual targets recognize only certain classes of drug The fewer the type of receptors a drug can bind, the greater or higher the drug’s specificity No drugs are completely specific in their actions. In many cases, the dose of a drug will cause it to affect targets other than the principal one, and this can lead to side effects. Low specificity increases chance of side effects (due to off-target interactions) The chemical structure of a drug determines its: Affinity for its receptor Intrinsic activity Drug specificity RELATION BETWEEN DRUG CONCENTRATION AND EFFECT DOSE RESPONSE CURVE (OR CONCENTRATION-RESPONSE) Refers to the relationship between an effect of a drug and the amount of drug given Dose-response curve, is a depiction of the observed effect of a drug as a function of its concentration in the receptor compartment DOSE RESPONSE CURVE PHASES First Phase: the curve is flat as the amount of drug given is not great enough to initiate a response Threshold - the first point along the graph where a response above zero is reached Potency a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect Second Phase: the curve steadily rises (Slope). With each increase in the drug dose, there is also an increased in desired response Third Phase: the curve plateaus at the top (Maximal Efficacy), indicating that any further increases in drug dose will not increase a drug response IMPORTANCE OF DOSE RESPONSE CURVE Dose response curves are essential to understand the drug's safe and hazardous levels, so that the therapeutic index can be determined, and dosing guidelines can be created The therapeutic index (also referred to as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity; ratio Narrow therapeutic range = having little difference between toxic and therapeutic doses MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS: RELATIONSHIP BETWEEN OCCUPANCY AND RESPONSE In a linear relationship, 50 % of the total receptor population must be occupied to achieve 50 % of the maximal organ system response. It follows then that a maximal response will occur only when all receptors are occupied. In most human systems the relationship between receptor occupancy and drug response is hyperbolic. Because of this hyperbolic relationship between occupancy and response, maximal responses are achieved at less than maximal receptor occupancy. Spare Receptors A certain number of receptors are “spare.” Spare (reserve) receptors are receptors that exist in excess of those required to produce a full effect. Biological Significance The spare receptor concept could explain why the sensitivity of tissue depend on both affinity of drug & total number of receptor It is possible to change the sensitivity of tissue with spare receptor by altering receptor concentration Agonist can still produce an undiminished maximal response in presence of an irreversible antagonist Two Phenomena Account For The Amplification Of The Ligand - Receptor Signal A single ligand–receptor complex can interact with many G proteins - multiplying the original signal to many-fold The activated g proteins persist for a longer duration than the original ligand - receptor complex  DESENSITIZATION AND RELATED CONCEPTS Desensitization refers to the common situation where the biological response to a drug diminishes when it is given continuously or repeatedly may be possible to restore the response by increasing the dose (or concentration) of the drug Tachyphylaxis - desensitization that occurs very rapidly, over few minutes or hours depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g., a stored neurotransmitter released from a nerve terminal), or receptor phosphorylation Tolerance - conventionally used to describe a more gradual loss of response to a drug that occurs over days or weeks development of counter--regulatory physiological changes that offset the actions of the drug (e.g., accumulation of salt and water in response to vasodilator therapy), or reduction of target receptor numbers  TYPES OF TOLERANCE Metabolic/dispositional tolerance – due to changes (increases) in liver enzymes (liver enzyme induction) which leads to more rapid/complete biotransformation of drug Neuronal/cellular/physiological/pharmacodynamic tolerance - most likely due to changes (“down regulation” usually) in the number of receptor sites on neurons Behavioral tolerance - learned behavioral adjustments that compensate for drug effects, which then looks like the drug is having less of an effect Cross-tolerance - resistance to the effects of a substance because of exposure to a pharmacologically similar substance usually thought to be caused by liver enzyme induction  Refractoriness - state where there is lack of responsiveness to a drug Drug resistance - term normally reserved to describe the loss of effectiveness of an antimicrobial or cancer chemotherapy drug  MECHANISMS FOR DEVELOPMENT OF DRUG RESISTANCE Change in receptors Conformational change Phosphorylation - interferes with the ability to activate second messenger cascades Translocation of receptors Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface, as a result of internalization of the receptors  Exhaustion of mediators – depletion of an essential intermediate substance Increased metabolic degradation of the drug Physiological adaptation Active extrusion of drug from cells (mainly relevant in cancer chemotherapy)  FACTORS MODIFYING DRUG ACTION Low specificity Some drugs are administered as racemic mixtures of stereoisomers; stereoisomers can exhibit different pharmacodynamic as well as pharmacokinetic properties Drug access to target tissues Drug concentration in different tissues Pharmacogenetics  Interactions with other drugs Drug interactions may be pharmacokinetic (the delivery of a drug to its site of action is altered by a second drug) or pharmacodynamic (the response of the drug target is modified by a second drug) Interactions can be synergistic, additive, or antagonistic Chronic administration of a drug causes a down-regulation or desensitization of receptors that can require dose adjustments to maintain adequate therapy. Rapid development of complete tolerance, a process known as tachyphylaxis Drug resistance due to pharmacokinetic mechanisms  Act on Receptors That Affect Concentrations of Endogenous Ligands A large number of drugs act by altering the synthesis, storage, release, transport, or metabolism of endogenous ligands such as MECHANISMS neurotransmitters, hormones, and OF DRUG other intercellular mediators. ACTIONS Act on Receptors That Regulate the Ionic Milieu A relatively small number of drugs act by affecting the ionic milieu, e.g., pH, electrolyte concentrations, of blood, urine, and the GI tract. The receptors for these drugs are ion pumps and transporters  Act on Receptors that Activate Cellular Pathways Act on Receptors that are responsible for Signal Integration and Amplification END