Drug Receptor Interactions and Pharmacodynamics

Transcription

1 Drug Receptor Interactions and Pharmacodynamics Dr. Raz Mohammed MSc Pharmacology School of Pharmacy Lec 6

2 Pharmacodynamics definition Pharmacodynamics describes the actions of a drug on the body and the effect of drug concentrations on the magnitude of response. Drugs exert their effects by interacting with receptors present on the cell surface or within the cell.

3 The drug-receptor complex Cells have different types of receptors, each is specific for a particular ligand and produces a unique response. Ligand: A small molecule that binds to a receptor, it may be a naturally occuring molecule or a drug. Cells may have tens of thousands of receptors for certain ligands (drugs). Cells may also have different types of receptors, each of which is specific for a particular ligand (drug). Example: the heart contains specific receptors that bind and respond to norepinephrine, also receptors for acetylcholine.

4 The recognition of a drug by a receptor triggers a biologic response

5 The formation of the drug-receptor complex leads to a biologic response. The magnitude of the response is proportional to the number of drug-receptor complexes: Most receptors are named to indicate the type of drug/chemical that interacts best with it; for example, the receptor for histamine is called a histamine receptor. Not all drugs exert their effects by interacting with a receptor; for example, antacids chemically neutralize excess gastric acid, reducing the symptoms of heartburn

6 Major Receptor Families A. Transmembrane Ligand-gated ion channels B. Transmembrane G protein-coupled receptors C. Enzyme-linked receptors D. Intracellular receptors

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8 A. Transmembrane Ligand-gated ion channels These are responsible for regulation of the flow of ions across cell membranes. The activity of these 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. The nicotinic receptor and the (GABA) receptor are important examples of ligandgated receptors

9 These receptors mediate functions such as neurotransmission, cardiac conduction, and muscle contraction. EX. stimulation of the nicotinic receptor by Ach results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell.

10 Nicotinic receptor

11 GABA receptor

12 B. Transmembrane G protein-coupled receptors These receptors consist of a single peptide that has seven membrane-spanning regions. Intracellularly, these receptors are linked to a G protein having three subunits an { α } subunit that binds (GDP) and { β, γ } subunit.

13 Binding of the ligand to the receptor results in the following: Activation of the G protein so that GTP replaces GDP on the α subunit. Dissociation of the G protein occurs, and both α- GTP subunit and β γ subunit subsequently interact with other cellular effectors ( enzyme or ion channel). These effectors then activate second messengers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes.

14 G protein-coupled receptors are the most abundant type of receptors. Important processes mediated by G protein coupled receptors include neurotransmission, olfaction, and vision. Example of receptors: α and ß adrenergic receptors muscarinic receptors

15 Second messengers: These are intracellular signaling molecules released by the cell to trigger physiological changes, they are essential in conducting & amplifying signals coming from G protein coupled receptors. 1. Activation of adenylyl cyclase by α-gtp subunits, results in the production of camp a second messenger that regulates protein phosphorylation. 2. G proteins also activate phospholipase C, which is responsible for the generation of two other second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 is responsible for the regulation of intracellular free calcium concentrations. DAG activates several enzymes such as protein kinase C leading to countless physiological effects.

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18 The recognition of chemical signals by G protein-coupled membrane receptors triggers an increase in the activity of adenylyl cyclase.

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21 C. Enzyme-linked receptors (Receptor Tyrosine kinase) These receptors have cytosolic enzyme activity as an integral component of their structure or function. Binding of a ligand to an extracellular domain activates this cytosolic enzyme activity. Duration of responses to stimulation of these receptors is on the order of minutes to hours. Example of receptor: insulin. These receptors have a tyrosine kinase activity as part of their structure. Upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form.

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24 Insulin Receptor

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26 D. Intracellular receptors The fourth family of receptors is different from the other three in that the receptor is entirely intracellular and the ligand must diffuse into the cell to interact with the receptor. The ligand in that it must have sufficient lipid solubility to be able to move across the target cell membrane. For example, steroid hormones exert their action on target cells by this receptor mechanism. The ligand binds with its receptor, and the receptor becomes activated The activated ligand receptor complex migrates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression.

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28 Mechanism of intracellular receptors

29 The duration of the response (hours to days) is much greater than that of other receptor families. Other examples of intracellular ligands and their targets?

30 Characteristics of signal transduction Signal transduction has two important features: 1. The ability to amplify small signals 2. Mechanisms to protect the cell from excessive stimulation.

31 1. Signal amplification Some receptors have the ability to amplify signal duration and intensity. G protein linked receptors amplifies many of possible responses initiated by ligand binding to a receptor. Two phenomena account for the amplification First, a single ligand receptor complex can interact with many G proteins, multiplying the original signal many-fold. Second, the activated G proteins persist for a longer duration than the original ligand receptor complex.

32 A drug can produce a maximal response even when less than 100% of the receptors are occupied. The remaining unoccupied receptors are just serving as receptor reserve are called Spare receptors.

33 2. Desensitization and downregulation of receptors: Repeated or continuous administration of an agonist may lead to changes in the responsiveness of the receptor. To prevent potential damage to the cell, several mechanisms have evolved to protect a cell from excessive stimulation. Tachyphylaxis (desensitization): Repeated administration of a drug results in a diminished effect. The receptor becomes desensitized to the action of the drug, the receptors are still present on the cell surface but are unresponsive to the ligand.

34 Down-regulation: Prolonged exposure to high concentration of agonist causes a reduction in the number of receptors available for activation. This results due to endocytosis or internalisation of the receptors from the cell surface. These receptors may be recycled to the cell surface, restoring sensitivity, or may be degraded, decreasing the total number of receptors available. Some receptors, require a (resting period) following stimulation before they can be activated again. During this recovery phase they are said to be (refractory) or (unresponsive).

35 Some receptors, require a (resting period) following stimulation before they can be activated again. During this recovery phase they are said to be (refractory) or (unresponsive). Desensitization of receptors

36 Potency Is the amount of drug necessary to produce an effect of a given magnitude. EC50 : is the concentration of drug producing an effect that is 50 % of the maximum. It is used to determine potency; it is commonly designated as the EC50. In the figure, the EC50 for Drugs A and B are indicated. Drug A is more potent than Drug B because less Drug A is needed to obtain 50 percent effect

37 The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph. Panel B is a semilogarithmic plot of the same data. EC50 = drug dose that shows fifty percent of maximal response.

38 Efficacy [intrinsic activity]: This is the ability of a drug to produce a physiologic response (effect) when it interacts with a receptor. Efficacy is dependent on the number of drugreceptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses. Maximal response (Emax) is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than one that is more potent.

39 Typical dose-response curve for drugs showing differences in potency and efficacy. (EC50 = drug dose that shows fifty percent of maximal response.)

40 Affinity Affinity describes the strength of the interaction (binding) between a ligand and its receptor. Kd: is the dissociation constant for the drug from the receptor, can be used to determine the affinity of a drug for its receptor. - The higher the Kd value, the weaker the interaction and the lower the affinity. - when a drug has a low Kd, the binding of the ligand to the receptor is strong, and the affinity is high.

41 AGONIST 1. Full agonist 2. Partial agonist 3. Inverse agonist

42 Agonists An agonist binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand. 1. Full agonist: A full has a strong affinity for its receptor and maximum efficacy. A drug binding to a receptor and producing 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.

43 2. Partial agonist Have efficacies greater than zero, but less than that of a full agonist. -Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist. -In the presence of agonist, a partial agonist act as an antagonist.

44 Effects of full agonists, partial agonists, and inverse agonist on receptor activity.

45 3. Inverse agonist A drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.

46 Antagonist Drugs that decrease or oppose the actions of another drug or endogenous ligand. An antagonist has no effect if an agonist is not present Many antagonists act on the same receptor as the agonist. Have no intrinsic activity and produce no effect (no efficacy),but they have strong affinity to the receptor.

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48 Types of antagonist 1- Competitive antagonist: Both antagonist and agonist bind to the same site on the receptor. The competitive antagonist prevents an agonist from binding to its receptor. Example: Terazosin If the agonist is given in a high enough concentration, it can displace the antagonist and fully activate the receptors. 2- Irreversible antagonist: Irreversibly (permanently) binds to the receptor The effects of an irreversible antagonist cannot be overcome by adding more agonist.

49 3. Chemical antagonist is a drug that interacts directly by combining with another drug and rendering it inactive. Protamine sulfate ionically binds to heparin, rendering it inactive and antagonizing heparin's anticoagulant effect. 4. Physiologic antagonist (functional antagonist) An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. Example/ Functional antagonism by epinephrine to histamine induced bronchoconstriction. Histamine receptor on bronchial smooth muscle causing contraction and narrowing of bronchial smooth muscle, epinephrine is an agonist at beta 2 receptor on bronchial smooth muscle lead to relaxation of muscles.

50 Therapeutic index Is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals. Therapeutic index=td50/ ED50 TD50 = the drug dose that produces a toxic effect in half the population ED50 = the drug dose that produces a therapeutic or desired response in half the population. Therapeutic index is a measure of a drug's safety, a larger value indicates a wide margin between doses that are effective and doses that are toxic. Warfarin ( have a small therapeutic Index). Penicillin ( have a large therapeutic index) is safe.

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