4 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;neurotransmissioncardiac conductionmuscle contraction etc...Cholinergic nicotinic receptors is an example to these type of receptors.
15 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.MetabolismGrowthDifferentiationDuration of responses to stimulationimportant functions controlled by these receptors.Most Common Enzyme-Linked ReceptorsEGFPDGF tyrosine kinase activityANPInsulinminutes to hours
18 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 proteinsSteroid 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.
20 DRUG-RECEPTOR INTERACTIONS CHAPTER II: DOSE-RESPONSE RELATIONSHIPSAsst. Prof. Dr. Emre HamurtekinEMU Faculty of Pharmacy
21 GRADED DOSE-RESPONSE RELATIONS As the concentration of a drug increases, the magnitude of its pharmacological effect also increases.
22 GRADED DOSE-RESPONSE RELATIONS Two important properties of drugs can be determined by graded-dose response curves;POTENCYEFFICACYPOTENCY:Measure of the amount of drug necessary to produce an effect of a given magnitude.Concentration of drug producing an effect that is 50% of the maximum effect (EC50)
24 GRADED DOSE-RESPONSE RELATIONS 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 formedefficiency 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.
27 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 affinityLow Kd: strong interaction-high affinityAs the concentration of free drug increases, the ratio of the concentrations of bound receptors to total receptors approaches unity.=
28 DRUG BINDING and PHARMACOLOGIC EFFECT [E] [D][Emax] Kd+[D]ASSUMPTIONS:Binding exhibits no cooperativity.Magnitude of the response is proportional to the amount of bound receptors.Emax occurs when all receptors are bound.=
29 AGONISTSAn agonist binds to a receptor and produces a biological response.Full agonistsPartial agonistsInverse agonistsFull 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 itsactive state.phenylephrineα-1 adrenoceptorsBPrisesCa
30 PARTIAL AGONISTPartial 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.
32 INVERSE AGONISTThey 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.
34 ANTAGONISTSAntagonists 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 antagonistsNon-competetive (irreversible) antagonistsCompetetive 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.Covalent binding to the active site of the receptorAllosteric binding
36 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.Example: Histamine vs. Epinephrine on bronchiolesChemical antagonism: Prevents the actions of an agonist by modifying or sequestering the agonist, thus agonist can not bind and activate its receptor.Example: Heparine (acidic)vs. Protamine sulphate (basic)
37 THERAPEUTIC INDEX (TI) It is the ratio of the dose that produces toxicity to the dose that produces effective response.TI = TD50 / ED50Therapeutic index is a measure of drug safetySmall therapeutic index: WarfarinLarge therapeutic index: Penicilin