Dr. Mahmoud H. Taleb 1 بسم الله الرحمن الرحيم Pharmacology I for dental students Lecture 5 Signal transduction and second messengers

Dr. Mahmoud H. Taleb2 Signal Transduction and Second Messengers Stimulating cardiac membranes with epinephrine increased the concentration of a water-soluble nucleotide, cyclic adenosine monophosphate (cAMP), and they proposed that the cAMP acted as an intracellular messenger. Stimulation of cells by first messengers ( hormones and neurotransmitters), which can not traverse the lipid plasma membrane, results in the regulation of a variety of intracellular compounds, called second messengers.

Dr. Mahmoud H. Taleb3 Second messengers Second messengers are small molecules generated in response to occupation of a receptor by its extracellular ligand. The compounds produced interact with intracellular proteins to regulate cell function.

Dr. Mahmoud H. Taleb4 There are four basic mechanisms by which extracellular ligands regulate intracellular processes : 1- The most complex are the G protein coupled receptor system, composed of a transmembrane receptor that binds a ligand on its extracellular surface and couples to a guanine-nucleotide- binding protein ( G protein) on its intracellular surface. 2- The receptor tyrosine kinase and receptor guanyl cyclase systems. 3- The simplest system are those of ligand- gated ion channels. 4- Ligands that are suffiently lipid soluble to cross the membrane can bind to intracellular receptors

Dr. Mahmoud H. Taleb5 Receptor signaling pathways Effectors Second messenger Adenylate cyclase(AC) CAMP Guanylate cyclase (Gc) CGMP Phospholipase C ( PLC) DAG and IP3 Phospholipase A(PLA2) Arachidonic acid Nitric oxide Synthase NO and CO IONS Na +, Ca 2+, K +, Cl -

Dr. Mahmoud H. Taleb6 Endogenous compounds act on their receptors ** Neurtransmitter ** Neuropeptides ** Hormones ** Ions

Dr. Mahmoud H. Taleb7 Types of Receptors Membrane bound receptor * G- Protein- linked receptors sertonin, Muscarinic, Dopaminergic, Noradrenergic * G- Protein- linked receptors sertonin, Muscarinic, Dopaminergic, Noradrenergic * Enzyme receptors * Enzyme receptors Tyrosine kinase Tyrosine kinase Ligand- gated ion channel receptors Nicotine, GABA, glutamate Ligand- gated ion channel receptors Nicotine, GABA, glutamate Intracellular receptors Intracellular receptors Sufficiently lipid soluble to cross the plasma membrane by binding to a group of intracellular proteins known as steroid receptor Sufficiently lipid soluble to cross the plasma membrane by binding to a group of intracellular proteins known as steroid receptor

Dr. Mahmoud H. Taleb8 G protein-coupled second – messenger system Most hormones and a few neurotransmitters act by regulating intracellular second messengers through G protein- coupled receptor. The three component of each system-receptor, G protein, and effector enzyme G Proteins G Proteins that transduce signals from membrane receptors to effector enzymes and ion channels are known as the heterotrimetric G proteins. Each of these proteins is composed of three distinct subunits, termed α,β and ð.

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Dr. Mahmoud H. Taleb11 Figure 2.2 Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.

Dr. Mahmoud H. Taleb12 Dose Response Relationships   An agonist is defined as an agent that can bind to a receptor and elicit a biologic response.   The magnitude of the drug effect depends on the drug concentration at the receptor site, which in turn is determined by the dose of drug administered and by factors characteristic of the drug pharmacokinetic profile, such as rate of absorption, distribution, and metabolism.

Dr. Mahmoud H. Taleb13 Properties of Log –dose response 1- Describes LDR relationship over a wide of doses. 2- Suitable for evaluation of concentration. 3- The same effect is produced by different drugs acting with similar mechanism.

Dr. Mahmoud H. Taleb14 An interpretation of LDR curve receptor occupancy Theory of drug action Intensity is direct proportional with occupation All – or – none effect All – or – none effect A given dose of a drug either has or has not evoked a certain effect in the subjects. e.g. death, convulsion

Dr. Mahmoud H. Taleb15 Histogram and cumulative frequency plots When the dose is varied, the nunber of subjects responding can be plotted against. Median effective and median lethal dose ED 50, LD50

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Dr. Mahmoud H. Taleb17 A. Graded dose response relations As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. The relationship between dose and response is a continuous one, and it can be mathematically described for many systems by application of the law of mass action, assuming the simplest model of drug binding:   The response is a graded effect, meaning that the response is continuous and gradual. This contrasts with a quantal response, which describes an all-or-nothing response. A graph of this relationship is known as a graded   Dose response curve. Plotting the magnitude of the response against increasing doses of a drug produces a graph that has the general shape depicted in Figure 2.6A. The curve can be described as a rectangular a very familiar curve in biology because it can be applied, to diverse biological eventssuch as ligand binding, enzymatic ctivity, and responses to pharmacologic agents.

Dr. Mahmoud H. Taleb18   Potency: Two important properties of drugs can be determined by graded dose response curves. The first is potency, a measure of the amount of drug necessary to produce an effect of a given magnitude. For a number of reasons, the concentration producing an effect that is fifty percent of the maximum is used to determine   potency; it 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. Thus, therapeutic preparations of drugs will reflect the potency.

Dr. Mahmoud H. Taleb19   Efficacy [intrinsic activity]: The second drug property that can be determined from graded dose response plots is the efficacy of the drug. This is the ability of a drug to illicit a physiologic response when it interacts with a receptor. Efficacy is dependent on the number of drug- receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses. Analogous to the maximal velocity for enzyme catalyzed reactions, the maximal response (Emax) or efficacy is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than one that is more potent. Figure 2.7 shows the response   to drugs of differing potency and efficacy.

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Dr. Mahmoud H. Taleb21   Quantal Dose Response Relationships Another important dose response relationship is that of the influence of the magnitude of the dose on the proportion of a population that responds. These responses are known as quantal responses, because, for any individual, the effect either occurs or it does not. Even graded responses can be considered to be quantal if a predetermined level of the graded response is designated as the point at which a response occurs or not. For example, a quantal dose response relationship can be determined in a population for the antihypertensive drug   atenolol. A positive response is defined as at least a 5 mm Hg fall in diastolic blood pressure. Quantal   Dose response curves are useful for determining doses to which most of the population responds.

Dr. Mahmoud H. Taleb22 Pharmacokinetics This deals with ADME

Dr. Mahmoud H. Taleb23 Drug solubility and Absorption Routes of drug administration. Choice of route…. must depend on therapeutic objectives. During its transport from site of administration to systemic circulation, the drug crosses many cell membranes, Absorption. Part of the drug may be metabolized before reaching the systemic circulation first pass metabolism & is eventually lost. The remaining fraction which is succeeded to reach the systemic circulation is called the Bioavailability.

Dr. Mahmoud H. Taleb24 Factors which affect absorption of drugs 1- Factors related to the dosage form. 2- Factors related to the drug. As M.W. and solubility coefficient of the drug. 3- Factors affecting stability of the drug in gut contents 4- PH of the gut in relation to the pk a of the drug affect ionization of the molecules into ions. 5- Factor related to absorptive system.

Dr. Mahmoud H. Taleb25 Factors affecting first – pass metabolism of drugs 1- The route of administration of the drugs. Hepatic first pass effect can be comletely avoided by parentral or sublingual administration, rectal administration did not completely eliminate the hepatic first pass effect since the blood supply of the upper third of the rectum passes to the liver through the mesentric circulation. 2- The nature of the drug. *** Hepatic first- metabolism occutr for drugs whose liver metabolism is very active e.g. nitroglycerin. *** Hepatic first- metabolism occutr for drugs whose liver metabolism is very active e.g. nitroglycerin. *** Pulmonary first pass metabolism e.g. opoids

Dr. Mahmoud H. Taleb26 3- Hepatic first pass metaboism is largely reduced in situations associated with --- Decrease of the portal blood flow e.g. portal hypertension, treatment with --- Decrease of the portal blood flow e.g. portal hypertension, treatment with ----Inhibition of the hepatic enzyme activity e.g. cimitidine, chlormphenicol ----Inhibition of the hepatic enzyme activity e.g. cimitidine, chlormphenicol

Dr. Mahmoud H. Taleb27 2- Distribution After absorption. The drug is carried by the blood to various body organs. The amount of the drug delivered to each organ depends on the rate of blood flow to that organ. Some of drug molecules are carried bound to plasma proteins where the large drug- albumin complex can not enter the organ. Distribution may be roughly described by ag global parameter called apparent volume of disribution V d = amount of drug in the body/ plasma or blood concentration of the drug

Dr. Mahmoud H. Taleb28 Factors affecting Vd 1- Plasma protein binding. 2- Lipophilicity 3- Tissue binding

Dr. Mahmoud H. Taleb29 C- Elimination Lipid soluble drugs are eliminated by hepatic metabolism while water soluble drugs are eliminated mainly by renal excertion. Metabolism The aim of drug metabolism is to convert lipid drugs into water- soluble metabolites that can be easily excreted, sometimes metabolism leads to activation of drugs or change degree of activity and the most important metabolizing enzyme system is the hepatic microsomal enzyme systems P450. ( N.B.) and metabolism may varied.

Dr. Mahmoud H. Taleb30 Excretion Routes of excretion: 1- The kidney by two methods 2- Other sites for excretion -- Lung -- Saliva -- Bile -- Milk