Drug Receptors Pharmacodynamics Dr Hayder B Sahib Ph

Drug -Receptors & Pharmacodynamics Dr. Hayder B Sahib Ph. D. (Pharmacology) 15 September 2020 1

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RECEPTORS • Receptors are the specific molecules in a biologic system with which drugs interact to produce changes in the function of the system. • Receptors must be selective in their ligand-binding characteristics (so as to respond to the proper chemical signal and not to meaningless ones). • Receptors must also be modifiable when they bind a drug molecule (so as to bring about the functional change). 15 September 2020 7

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EFFECTORS • Effectors are molecules that translate the drugreceptor interaction into a change in cellular activity. • The best examples of effectors are enzymes such as adenylyl cyclase. • Some receptors are also effectors in that a single molecule may incorporate both the drug-binding site and the effector mechanism. For example, a tyrosine kinase effector is part of the insulin receptor molecule, and a sodiumpotassium channel is the effector part of the nicotinic acetylcholine receptor. 15 September 2020 10

GRADED DOSE-RESPONSE RELATIONSHIPS • When the response of receptor-effector system is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration or dose is called a graded dose-response curve. • The efficacy (Emax) and potency (EC 50 or ED 50) parameters are derived from these data. • The smaller the. EC 50 (or ED 50), the greater the potency of the drug. 15 September 2020 11

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B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC 50, whereas the maximal effect is Emax. 15 September 2020 13

GRADED DOSE-BINDING RELATIONSHIP & BINDING AFFINITY • If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained. • The concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax. 15 September 2020 14

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• The smaller the Kd, the greater the affinity of the drug for its receptor. • If the number of binding sites on each receptor molecule is known, it is possible to determine the total number of receptors in the system from the Bmax. (drug-receptor binding) • Drug + Receptor ↔ Drug–receptor complex → Biologic effect 15 September 2020 16

QUANTAL DOSE-RESPONSE RELATIONSHIPS • is defined as the minimum dose required to produce a specified response is determined in each member of a population. • Quantal dose-response plots from a study of therapeutic and lethal effects of a new drug in mice. • The median effective (ED 50), median toxic (TD 50), and (in animals) median lethal (LD 50) doses are derived from experiments carried out in this manner. 15 September 2020 17

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Quantal dose-response data provide information about the variation in sensitivity to the drug in a given population, and if the variation is small, the curve is steep. 15 September 2020 19

• Efficacy: the ability of a drug to elicit a response when it interacts with a receptor. Efficacy is dependent on the number of drug– receptor complexes. Efficacy is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than one that is more potent. Maximal efficacy assumes that all receptors are occupied by the drug, and no increase in response will be observed if more drugs are added. This concept holds true only if there are no "spare receptors" 15 September 2020 20

• Potency: The concentration of drug producing an effect that is 50 percent of the maximum( EC 50). • Potency is determined mainly by the affinity of the receptor for the drug and the number of receptors available. • In quantal dose response measurements, ED 50, TD 50, and LD 50 are also potency variables (median effective, toxic, and lethal doses, respectively) 15 September 2020 21

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SPARE RECEPTORS • Spare receptors are exist if the maximal drug response (Emax) is obtained at less than 100% occupation of the receptors (Bmax). • If the EC 50 is ˂ Kd, spare receptors are said to exist. 15 September 2020 24

SPARE RECEPTORS • This might result from 1 of 2 mechanisms. First: the duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction. Second: the actual number of receptors may exceed the number of effector molecules available. • The presence of spare receptors increases sensitivity to the agonist 15 September 2020 25

AGONISTS, PARTIAL AGONISTS, & INVERSE AGONISTS • receptor to have at least 2 states—active (Ra) and inactive(Ri). • Many receptor systems exhibit some activity in the absence of ligand, called constitutive activity. • Full agonist a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand • For example, phenylephrine is an agonist at α 1 adrenoceptors, because it produces effects that resemble the action of the endogenous ligand, norepinephrine. 15 September 2020 26

• Partial agonist A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist. • Partial agonists have efficacies (intrinsic activities) greater than zero but less than that of a full agonist. • In the presence of a full agonist, a partial agonist acts as an inhibitor. • In contrast, inverse agonists have a much higher affinity for the inactive Ri state than for Ra and decrease or abolish any constitutive activity. 15 September 2020 27

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ANTAGONISTS • A. Competitive and Irreversible Pharmacologic Antagonists • If both the antagonist and the agonist bind to the same site on the receptor, they are said to be “competitive. ” • The competitive antagonist will prevent an agonist from binding to its receptor and maintain the receptor in its inactive conformational state. • For example, the antihypertensive drug terazosin competes with the endogenous ligand, norepinephrine, at α 1 adrenoceptors, thus decreasing vascular smooth muscle tone and reducing blood pressure. 15 September 2020 29

• Irreversible antagonists • An irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present. • The effects of competitive antagonists can be overcome by adding more agonist. • Irreversible antagonists, by contrast, cannot be overcome by adding more agonist. • Competitive antagonists increase the ED 50, whereas irreversible antagonists do not (unless spare receptors are present). 15 September 2020 30

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• There are two mechanisms by which an agent can act as a noncompetitive antagonist. I. The antagonist can bind covalently or II. with very high affinity to the active site of the receptor (irreversible antagonist). The second type of antagonist binds to a site ("allosteric site") other than the agonist binding site. This allosteric antagonist prevents the receptor from being activated even when the agonist is attached to the active site. 15 September 2020 32

• B. Physiologic Antagonists • A physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes. • Thus, it differs from a pharmacologic antagonist, which interacts with the same receptor as the drug it inhibits. • Familiar examples of physiologic antagonists are the antagonism of the bronchoconstrictor action of histamine by epinephrine’s bronchodilator action. 15 September 2020 33

• C. Chemical Antagonists • A chemical antagonist interacts directly with the drug being antagonized to remove it or to prevent it from binding to its target. • A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur). • Common examples of chemical antagonists are dimercaprol, a chelator of lead and some other toxic metals, and pralidoxime, which combines with the phosphorus in organophosphate cholinesterase inhibitors. 15 September 2020 34

THERAPEUTIC INDEX & THERAPEUTIC WINDOW v. Is a measure which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect vdenotes the safety of the drugs v. TI=LD 50 /ED 50 （LC 50 /EC 50 ） • The larger value of the TI is, the wider margin between effective dose and toxic dose is. For example, the drug of TI=4 is more safe than that of TI=2. 15 September 2020 35

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SIGNALING MECHANISMS • The receptor-effector system may be 1) ligand-gated ion channels, eg. Cholinergic nicotinic receptors. 2) G protein–coupled receptors , eg. alpha and beta adrenoceptors. 3) enzyme–linked receptors, eg. Insulin receptors. 4) intracellular receptors, eg. Steroid receptors. 15 September 2020 37

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1 - Transmembrane ligand-gated ion channels: The first receptor family comprises ligand-gated ion channels are responsible for regulation of the flow of ions across cell membranes. • The activity is regulated by the binding of a ligand to the channel. • Response to these receptors is very rapid (a few milliseconds). • These receptors mediate diverse functions, including neurotransmission, cardiac conduction, and muscle contraction. 15 September 2020 39

stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, on the other hand, enhance the stimulation of the γ-aminobutyric acid (GABA) receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. 15 September 2020 40

2. Transmembrane G protein–coupled receptors: v. These receptors are linked to a G protein (Gs, Gi, and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit v Binding of the ligand activates the G protein so that GTP replaces (GDP) on the α subunit. v. 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, a protein, or an ion channel. v Stimulation of these receptors results in responses that last several seconds to minutes. 15 September 2020 41

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Second messengers • The small molecule metabolite or ion. • Second messengers can diffuse through a cell and carry information to a wide variety of targets. • Well-studied second messengers include cyclic AMP and cyclic GMP, Ca 2+, phosphoinositides, and nitric oxide. 15 September 2020 43

• A. Cyclic AMP • Is the prototypical second messenger • Is synthesized by adenylyl cyclase under the control of many G protein-coupled receptors • The activity of adenylyl cyclase can be modulated by phosphorylation and other regulatory influences 15 September 2020 44

• B. Calcium and Phosphoinositides v. Phospholipase C splits the phosphatidylinositol-4, 5 - bisphosphate (PIP 2) into diacylglycerol (DAG) and inositol-1, 4, 5 trisphosphate (IP 3) v. DAG is limited to the membrane and activates a phospholipid- and calciumsensitive protein kinase (protein kinase C). v. IP 3 triggers release of Ca 2+ from internal storage vesicles 15 September 2020 45

3. Enzyme-linked receptors: • These receptors also have cytosolic enzyme activity as an integral component of their structure and function. • Duration of responses to stimulation of these receptors is on the order of minutes to hours. • The most common enzyme-linked receptors (epidermal growth factor, peptide, insulin, and others) that have a tyrosine kinase activity as part of their structure. 15 September 2020 46

4. Intracellular receptors: • the ligand must diffuse into the cell to interact with the receptor, & have lipid solubility to be able to move across the target cell membrane. • The activation or inactivation of these factors causes the transcription of DNA into RNA • and translation of RNA into a group of proteins. For example, steroid hormones exert their action on target cells via this receptor mechanism. 15 September 2020 47

RECEPTOR REGULATION • Frequent or continuous exposure to agonists results in short term diminution of the receptor response, sometimes called tachyphylaxis. • Several mechanisms are responsible for this phenomenon. 15 September 2020 48

• Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. • The opposite change (upregulation) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation. 15 September 2020 49