Pharmacodynamics PDF

Pharmacodynamics Esther T Menze Assoc. Prof. of Pharmacology and Toxicology Pharmacodynamics Pharmacodynamics describes the actions of a drug on the body PD studies topics such as Targets of the drug Mechanisms of action of a drug Dose/Response relationship...

Pharmacodynamics Esther T Menze Assoc. Prof. of Pharmacology and Toxicology Pharmacodynamics Pharmacodynamics describes the actions of a drug on the body PD studies topics such as Targets of the drug Mechanisms of action of a drug Dose/Response relationship (the influence of drug concentrations on the magnitude of the response ) Targets for Drug Action The protein targets for drug action on mammalian cells can be broadly divided into: Receptors Ion channels Enzymes Carrier molecules (transporters). Exceptions: Targets for chemotherapeutic drugs, where the aim is to suppress invading microorganisms or cancer cells, include DNA and cell wall constituents. Therapeutic Antibodies Most drugs exert their effects (both beneficial and harmful) by interacting with Receptors. These are, specialized target macromolecules present on the cell surface or within the cell that recognize and respond to endogenous chemical signals.  Drug-Receptor Interaction Receptor activation: the receptor is affected by the bound molecule in such a way as it elicit a tissue response. Endogenous mediator: NTs, Hormones, Cytokines Affinity and efficacy Receptor agonist: Bind to and activate the receptor (drug Bound Molecule or endogenous mediator) Affinity but no efficacy Receptor antagonist: Bind to the receptor without causing activation and prevent the binding of the agonist Affinity: the tendency of the drug to bind to the receptor Efficacy: the tendency to activate the receptor Drug-Receptor Interaction Theories I- Key-lock theory: only a drug of specific chemical structure can bind with the receptor (the shape of the ligand and the conformation of the active site of the enzyme are complementary) II-Induced fit theory: Receptors sometimes had to change their shape to accommodate the ligand (receptor undergoes conformational changes upon binding of the ligand and the shape of the active site becomes complementary to the ligand after binding). Major Receptor Families A. Ligand-Gated Ion Channels The activity of these ion channels is regulated by the binding of a ligand to the channel. Response to these receptors is very rapid, having durations of a few milliseconds. Examples: Nicotinic receptors -aminobutyric acid (GABA) receptors B.G-protein-Coupled Receptor Receptors coupled to G-protein They are the go-between proteins but were actually called G-proteins because of their interaction with the guanine nucleotides. G-proteins consist of three subunits: an  subunit that binds guanosine triphosphate (GTP) and a β subunit. Second messengers (ex. cAMP, IP3 and DAG) Response takes seconds to occur Ex: receptors of NE, dopamine, serotonin, acetylcholine).  Targets: Cardiac Ms contraction 1- Adenylyl cyclase Adenylyl cyclase Smooth Ms ATP cAMP relaxation Energy production (inc glucose and lipolysis) 2- Phospholipase C Gq Phosphatidyl inositol Phospholipase C Inositol triphosphate (IP3) and biphosphate (PIP2) Diacyl-glycerol (DAG) (inc Ca and so Ms contraction) G-protein variability is due to the α- subunit, accordingly G- protein can be Gs-------> Activate Adenylyl cyclase ( cAMP ) Gi--------> Inhibit Adenylyl cyclase ( cAMP) Gq--------> Activate Phospholipase C ( IP3 and DAG) C. Enzyme-Linked Receptors Binding of a ligand to an extracellular domain activates or inhibits a cytosolic enzyme activity. The most common enzyme-linked receptors are those that have a tyrosine kinase activity as part of their structure. Response may take hours Ex: Tyrosine-kinase-linked receptors such as receptors for insulin, growth factors and many cytokines  D. Nuclear Receptors The drug should diffuse into the cell to interact with receptor i.e. the drug should be lipid soluble. All operate through the same basic mechanism which depends on stimulation of transcription of selected genes leading to the synthesis of particular proteins and the production of cellular effects It takes time for onset of action i.e. time for protein synthesis and longer duration of action (hours). Ligands include steroid hormones, thyroid hormones, vitamin D & retinoic acid Receptor Characteristics The Life-Cycle of Receptors Expression: The cell runs the DNA program, which results in the creation of a receptor protein, and that receptor protein is then pushed out to the cell boundary and embedded in the cell's membrane. Down-regulation: receptors are taken out of the membrane and recycled into the cell. So fewer receptors are left on the cell membrane and therefore reduces the cell's sensitivity to the message Up-regulation: if the cell receives a weak signal, it can up-regulate by pumping out more receptors such as to increase the sensitivity to the weak message. Desensitization of receptors Repeated drug administration may change the responsiveness of the receptor to prevent potential damage to the cell. Tachyphylaxis: the receptors are still present on the cell membrane but unresponsive. Down-regulation: the receptors undergo endocytosis and sequestered from agonist interaction. Specificity For a drug to be useful, it must act selectively on particular cells and tissues. In other words, it must show a high degree of binding site specificity. Specificity is reciprocal: individual classes of drug bind only to certain targets, and individual targets recognize only certain classes of drugs. Absolute specificity: no drugs are completely specific in their actions. In many cases, increasing the dose of a drug will cause it to affect targets other than the principal one, and this can lead to side effects. Dose Response Relationships A. Graded dose-response relations The response is continuous and gradual. 1. Potency It is a measure of the amount of drug necessary to produce an effect of a given magnitude (EC50). 2. Efficacy (intrinsic activity) This is the ability of a drug to illicit a physiologic response when it interacts with a receptor (Emax). A drug with greater efficacy is more therapeutically beneficial than one that is more potent.  Agonist Full agonist Full agonist: Drug binds to a receptor (affinity) and produces a maximal biologic response (full efficacy) Partial agonist Drugs with intermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is submaximal. They bind (affinity) and activate the receptor but cannot produce maximal effect (partial efficacy). A unique feature of these drugs is that they can act as an antagonist of a full agonist. (i.e. in the presence of the full agonist) Inverse agonist It stabilize the inactive R form of the receptor or reduce the level of constitutive activation (negative efficacy). constitutive activation: an appreciable level of activation may exist even when no ligand is present (serotonin receptors). Antagonist  Antagonism 1. Competitive Antagonists 2. Non-competitive Both the antagonist and the The antagonist can The antagonist binds agonist bind to the same site bind covalently or to a site "Allosteric on the with very high affinity Site” other than the receptor, they are said to be to the active site of agonist binding site. “competitive” the receptor This will prevent the (Irreversible receptor from being Antagonist). activated even when This will reduce the the agonist is amount of receptors attached to the available to the active site. agonist  Drug Non- Competitive alone Competitive antagonist antagonist Emax: the maximum possible effect for the agonist ED50: which is defined as the dose producing a response that is 50 percent of the maximum obtainable. COMPETITIVE NON- COMPETITIVE ANTAGONIST ANTAGONIST Antagonist competes with the agonist for the Antagonist binds irreversibly to the recognition same recognition site of the receptor site of the receptor or bind to an allosteric site Duration of antagonism depends on the relative Duration of antagonism depends on the rate plasma concentrations of the agonist and the of turnover of the receptor molecule antagonist Causes parallel shift to the right in the dose Causes downward & non-parallel shift in the response curve and no change in Emax dose response curve & decrease in the Emax Reduce agonist Potency Reduce agonist Efficacy. Allosteric Effects In addition to the agonist binding site, to which competitive antagonists bind, receptor proteins possess many other, allosteric, binding sites through which drugs can influence receptor function in various ways, increasing or decreasing the affinity of agonists for the agonist binding site, or by modifying efficacy. Depending on the direction of the effect, the ligands may be allosteric antagonists or allosteric facilitators. examples of allosteric facilitation include the action of benzodiazepines on GABAA receptors. 3-Chemical antagonism: when two substances combine in solution; as a result, the effect of the active drug is lost. Examples Dimercaprol (chelating agent): bind to heavy metals and thus reduce their toxicity. Infliximab (anti-inflammatory): sequester the inflammatory cytokine, tumor necrosis factor. 4-Pharmacokinetic antagonism: when the ‘antagonist’ effectively reduces the concentration of the active drug at its site of action. Example Phenobarbital: reduce the anticoagulant effect of warfarin as it accelerates its hepatic metabolism. 5-Block of receptor–effector linkage Antagonist blocks at some point, downstream from the receptor, the chain of events that leads to the production of a response by the agonist. Example: Verapamil and nifedipine prevent the influx of Ca2+ through the cell membrane and thus block non-specifically the contraction of smooth muscle produced by other drugs. 6-Physiological/functional antagonism Physiological antagonism is a term used loosely to describe the interaction of two drugs whose opposing actions in the body tend to cancel each other. Example: 1- Histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump 2- Histamine and adrenaline  2) Quantal Dose–response The effect either occurs Relationships or it does not (all or non) This curve is obtained if the % of patients who respond to the drug is depicted against log the dose Therapeutic index It gives an idea about It is the ratio between ED50 & TD50 the drug safety i.e. Therapeutic index (TI) The TD50 is much higher = TD50/ED50 than ED50→ the drug is safe TD50 = the drug dose that produces toxic effect in half the population. ED50 = the drug dose that produces Warfarin : small TI a therapeutic desired response in Penicillin: high TI half the population.  ADVERSE DRUG REACTIONS Side effects (at therapeutic levels) Toxicity (overdose) Hypersensitivity (allergic reactions to the drug), immune-based adverse effects. Idiosyncracy (genetically mediated adverse effects) (Pharmacogenetic Disorders = genetic abnormalities that are revealed only by the effects of the drug e.g. succinylcholine apnea). Carcinogenicity, Mutagenicity, & Teratogenicity. Drug Abuse & Abstinence (withdrawal symptoms) Iatrogenic disease: drug-induced disease