TRANSMEMBRANE LIGAND-GATED ION CHANNELS These are responsible for regulation of the flow of ions across cell membranes. Response to these receptors is very rapid. Have role in; neurotransmission cardiac conduction muscle contraction etc... Cholinergic nicotinic receptors is an example to these type of receptors.
G PROTEIN-COUPLED RECEPTORS They are made of a single α – helical peptide that has seven membrane spanning regions.
G PROTEIN-COUPLED RECEPTORS
DAG Ca Second Messengers Essential in conducting and amplifying signals from G-protein coupled receptors. cAMP cGMP IP3
IP3 and DAG
ENZYME-LINKED RECEPTORS Spans the membrane once and may form dimers. These receptors also have cytosolic enzyme activity as an integral component of their structure. Metabolism Growth Differentiation Duration of responses to stimulation minutes to hours important functions controlled by these receptors. Most Common Enzyme-Linked Receptors EGF EGF PDGF tyrosine kinase activity PDGF tyrosine kinase activity ANP ANP Insulin Insulin
INTRACELLULAR RECEPTORS Receptor is entirely intracellular. Ligand must have sufficient lipid solubility. Ligands are mostly attached to plasma proteins in the blood circulation. Primary targets of these ligand-receptor complexes are transcription factors. DNA RNA proteins Steroid hormones exert their effects by this receptor mechanism. Time course of activation and duration of the response is much longer than the other type of receptors.
Asst. Prof. Dr. Emre Hamurtekin EMU Faculty of Pharmacy DRUG-RECEPTOR INTERACTIONS CHAPTER II: DOSE-RESPONSE RELATIONSHIPS
GRADED DOSE-RESPONSE RELATIONS As the concentration of a drug increases, the magnitude of its pharmacological effect also increases.
GRADED DOSE-RESPONSE RELATIONS Two important properties of drugs can be determined by graded-dose response curves; POTENCY EFFICACY POTENCY POTENCY: Measure of the amount of drug necessary to produce an effect of a given magnitude. EC50 Concentration of drug producing an effect that is 50% of the maximum effect (EC50)
GRADED DOSE-RESPONSE RELATIONS EFFICACY EFFICACY: Ability of a drug to elicit a response when it interacts with a receptor. Efficacy is dependent on; the number of drug-receptor complexes formed efficiency of the coupling of receptor activation to cellular responses. Maximal efficacy of a drug assumes that all receptors are occupied by the drug and if more drugs are added, no additive response will be observed. Maximal response (efficacy) is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than the one that is more potent.
DRUG CONCENTRATION and RECEPTOR BINDING [DR] [D] [Rt] Kd+[D] Kd can be used to determine the affinity of a drug for its receptor. Affinity: strength of interaction between a ligand and its receptor. High Kd: weak interaction-low affinity Low Kd: strong interaction-high affinity As the concentration of free drug increases, the ratio of the concentrations of bound receptors to total receptors approaches unity. =
DRUG BINDING and PHARMACOLOGIC EFFECT [E] [D] [Emax] Kd+[D] ASSUMPTIONS: 1. Binding exhibits no cooperativity. 2. Magnitude of the response is proportional to the amount of bound receptors. 3. Emax occurs when all receptors are bound. =
AGONISTS An agonist binds to a receptor and produces a biological response. 1. Full agonists 2. Partial agonists 3. Inverse agonists Full agonist:If a drug binds to a receptor and produces a maximal biological response that mimics the response to the endogenous ligand, it is known as a full agonist. Full agonist stabilizes the receptor in its active state. α -1 adrenoceptors phenylephrine Ca BP rises
PARTIAL AGONIST Partial agonist: Have efficacies greater then zero but less then that of a full agonist. A partial agonist may have an affinity that is greater than, less than or equivalent to that of a full agonist. Example: aripiprazole, an atypical neuroleptic agent.
INVERSE AGONIST They produce a response below the baseline responses measured in the absence of drug. This decreases the number of activated receptors to below observed in the absence of the drug. They exert the opposite pharmacological effect of receptor agonists.
ANTAGONISTS Antagonists are drugs that decrease the actions of another drug or an endogenous ligand. An antagonist has no effect if an agonist is not present. Antagonists produce no effect by themselves. Competetive antagonists Non-competetive (irreversible) antagonists Competetive antagonists: both the antagonist and agonist bind to the same site on the receptor. Non-competetive antagonists: An irreversible antagonist causes a downward shift of the maximum. And can not be overcome by adding more agonist. i. Covalent binding to the active site of the receptor ii. Allosteric binding
FUNCTIONAL and CHEMICAL ANTAGONISM Functional (physiological) antagonism: An antagonist may act at a completely separate receptor initiating effects that are functionally opposite those of the agonist. HistamineEpinephrine Example: Histamine vs. Epinephrine on bronchioles Chemical antagonism: Prevents the actions of an agonist by modifying or sequestering the agonist, thus agonist can not bind and activate its receptor. HeparineProtamine sulphate Example: Heparine (acidic) vs. Protamine sulphate (basic)
THERAPEUTIC INDEX (TI) It is the ratio of the dose that produces toxicity to the dose that produces effective response. TI = TD50 / ED50 Therapeutic index is a measure of drug safety Small therapeutic index: Warfarin Large therapeutic index: Penicilin