Pharmacodynamics MBBS Lecture Series 2022 PDF

PHARMACODYNATICS Dr Bassi PU MBBS, MSc, FMCP Consultant Physician/Clinical Pharmacologists MBBS Lecture Series Definition Pharmacodynamics: Is study of the biochemical and physiological effects of drugs as well as their mechanism of action. Simply. The study...

PHARMACODYNATICS Dr Bassi PU MBBS, MSc, FMCP Consultant Physician/Clinical Pharmacologists MBBS Lecture Series Definition Pharmacodynamics: Is study of the biochemical and physiological effects of drugs as well as their mechanism of action. Simply. The study of what the drug does to the body – The mechanism of drug actions in living tissues Mechanisms of action (“what the drug does to the body”) Therapeutics: Use of drugs for intended clinical benefits – cure of a disease, relief of symptoms etc. What is Pharmacodynamics? Pharmacodynamics is a branch of pharmacology that deals with the study of the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacodynamics: Basic Principles Mechanism of action of drugs Specific molecular processes by which drugs work, e.g. inhibition of an enzyme or stimulation of a receptor sub-type Mode of action of drugs General description of the type of action: e.g. supplements, antihypertensives, analgesics Site of action of drugs Specific organs, tissues or cells affected by the drug: e.g. sensory neurones; myocardium, bronchii, etc. How Do Drugs Work: By Protein targets for drug binding For drugs to exert their pharmacological effect, they must be bound to macromolecular components of a cell. Naturally occurring ligands act in the same way. There are four main types: Enzymes: Aspirin and cyclo-oxygenase Ion channels: Nimodipine and voltage- gated calcium channels Transporter proteins: Tricyclic antidepressants and the noradrenaline transporter  How Do Drugs Work (Mechanism of Action)? Fundamental premise of pharmacodynamics is ‘drug-receptor interactions’ Drugs can produce their actions by: 1) Binding with biomolecules (Receptor-mediated mechanisms): Biomolecules = Targets=Receptors Mostly protein in nature (protein target). 2) Non receptor-mediated mechanisms: Physiochemical properties of drugs. Within the organs of the body are specific receptors with which specific drugs can interact The analogy often used is ‘lock and key’: only drugs (chemicals) with the ‘correct’ molecular shape can interact with a particular receptor What are targets for drug binding ? Ion channels e.g. Sulfonylurea drugs (antidiabetic drugs): block K+ outflux via the K channels in pancreatic beta cells resulting in opening of calcium channels and insulin secretion.  What are targets for drug binding ? Carrier molecules The drug binds to such molecules altering their transport ability Responsible for transport of ions and small organic molecules between intracellular compartments, through cell membranes or in extracellular fluids. ¨ e.g., Na+,K+-ATPase inhibitor Example: Digoxin (Drug use in treatment of heart failure: blocks Na efflux via Na pump; used in  What are targets for drug binding ? Carrier molecules: Effect of cocaine Cocaine: blocks transport or reuptake of catecholamines (dopamine) at synaptic cleft The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. ¨ What are targets for drug binding ? Structural proteins ¨ e.g. tubulin is target for: Vincristine: anticancer agent Colchicine: used in treatment of gout Drug-Receptor Interaction Binding Forces between drugs and receptors Ionic bond. Van-Dar-Waal. Hydrogen bond. Covalent bond Drug-Receptor Interaction Affinity Ability of a drug to combine with the receptor. D + R → D-R complex Effect.→ ¨ Efficacy (Intrinsic Activity) Capacity of a drug receptor complex (D-R) to produce an action. is the maximal response produced by a drug (E max). Drug-Receptor Interaction Agonist Full agonist. Partial agonist Full Agonist Agonist: is a drug that combines with receptor and elicit a response (has affinity and efficacy). ¨ Antagonist: is a drug that combines with a receptor without producing responses. It blocks the action of the agonist (has affinity but no or zero efficacy). e.g. atropine Drug-Receptor Interaction Most conventional drugs are ‘agonists’ i.e. stimulate receptors or ‘antagonists’ i.e. block receptors For example, salbutamol (Ventolin®) is a beta-receptor stimulant; stimulation of beta-receptors in the lungs causes bronchodilation Metoprolol (Betaloc®) is a beta-receptor antagonist (‘blocker’); blockade of beta-receptors in the heart will slow rate and be ‘cardiprotective’. Note that by blocking the beta-receptors in the lungs  Drug-Receptor Interaction Partial Agonist : combines with its receptor & evokes a response as a full agonist but produces submaximal effect regardless of concentration (affinity & partial efficacy). e.g. pindolol A beta blocker which is a partial agonist, produces less decrease in heart rate than pure antagonists such as propranolol Mechanism of Action of Minerals/Vitamins/Supplements Not classic agonists/antagonists at specific receptors Generally, they are replacing or supplementing body stores, or enhancing effects in certain diseases and disorders Generally, they are co-factors or essential elements in normal metabolic and physiological processes  Metabolism Metabolism (biotransformation) is a process by which drugs are converted into more polar forms through a series of enzymatic reactions. This serves to increase the renal elimination of the substance. This usually, but not always, results in a less toxic form of the substance. Metabolites might still have potent biological activity (or might have toxic properties). An inactive or weakly active substance that has an active metabolite is called a prodrug. Elimination: Drug elimination is the irreversible removal or loss of a drug from the body. Metabolism and Elimination Metabolism Elimination Consists of elimination of Is the main mechanism of drug chemically unchanged drug or its elimination metabolites from the body Involves the enzymatic conversion - Occurs in the kidney Most drugs of one chemical entity to another leave the body in urine, either within the body unchanged or as polar Occurs predominantly in the liver metabolites Results in metabolites that are Also occurs at other sites such as more polar than the parent drug and that can be excreted by the the liver and the lungs kidneys  Example of Metabolism Barbital  Water soluble  Excreted unchanged  Theoretical and measured half-life of 55-75 hours Hexobarbital Lipophilic Metabolised Theoretical half-life of 2-5 months Measured half-life of 5-6 hours Sites of Drug Metabolism Metabolic enzymes are located in many different tissues and usually reflect tissues with a high exposure to xenobiotics. These include tissues of the: The Live, Lungs Nasal mucosa, Eye and - Gastrointestinal tract (GIT) The main site of biotransformation is the liver because of its size and concentration of enzymes. Sites of Drug Metabolism First-pass elimination Many xenobiotics are absorbed from the GIT by the liver and metabolised then. This is designed to prevent high levels of orally ingested xenobiotic reaching circulation. This first-pass metabolism can limit the bioavailability of some drugs. Alternative routes of administration avoid the first-pass effect. Notable drugs that experience a first-pass effect include; Stages in metabolism Phase I Phase II Introducesor exposes a Conjugation reactions functional group. –Glucuronidation - OH –Sulfation - NH2 –Acetylation –Methylation - SH –Glutathione conjugation - COOH –Amino acid conjugation Only slightly increases Generally, this produces a polarity large increase in polarity. Phase I metabolism There are three types of Phase I reaction: - Hydrolysis - Oxidation - Reduction Many Phase I products are not efficiently eliminated and may require a second conjugation reaction by Phase II enzymes to form a highly polar conjugate that can then be excreted in the urine.  Cytochrome P450 Cytochrome P450: Cytochrome P450 (CYP) is a haemeprotein that plays a key role in the metabolism of drugs and other xenobiotic. Cytochrome P450 (CYP450) enzymes are essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A2. They also are necessary for the detoxification of foreign chemicals and the metabolism of drugs. Cytochrome P450 proteins, named for the absorption band at 450 nm of their carbon-monoxide-bound form, are one of the largest superfamilies of enzyme proteins. The P450 genes (also called CYP) are found in the genomes of virtually all organisms, but their number has exploded in plants.  Cytochrome P450: Classification Cytochrome P450s are probably the most important primary Phase I metabolising enzymes because they have the: They are found in most tissues but their greatest concentration is in the liver. The microsomal pool of enzymes is especially important for metabolism. Understanding the CYP system is essential for advanced practitioners (APs), as the consequences of drug-drug interactions can be profound. Cytochrome P450s are classified by amino acid homology of the genes. Those with < 40% homology are put into separate families, with numbers as identifiers. Those with 40–55% homology have different sub-families and  Cytochrome P450: Classification Cytochrome P450s are classified by amino acid homology of the genes. Cytochrome P450 pathways are classified by similar gene sequences; they are assigned a family number (e.g., CYP1, CYP2) and a subfamily letter (e.g., CYP1A subfamily letter (e.g., CYP1A, CYP2D) and are then differentiated by a number for the isoform or individual enzyme (e.g., CYP1A1, CYP2D6).  Cytochrome P450: Classification In humans, they play central role in Phase 1 drug metabolism, drug -drug interactions, Inter-individual variation in drug metabolism and Genetic polymorphism resulting in marked metabolic activity e.g. CYP2D6 The p450 superfamily is believed to have originated from ancestral gene that existed over 3 billion years ago There are 74 families but only 17 families in humans. There are approximately 57 CYP genes. Cytochrome P450: Classification Important sub-families involved in drug metabolism are: CYP1A and CYP1B , CYP2A–D , CYP3A etc Role of sub-families Found in every class of organism, including Archaea. CYP1, CYP2 and CYP3 are found in the microsome and are involved in drug metabolism. CYP4 is found in the microsome but is involved in fatty acid metabolism.  CYP Structure Cytochrome P450s are haem-containing proteins. They usually require a second enzyme for catalytic activity – something that provides electrons. In the endoplasmic reticulum (ER), or primary metabolic enzymes, this is NADPH-cytochrome P450 reductase. Structure of cytochrome P450 (CYP3A4-PDB code 1TQN) with identified secondary structure elements (a-helices in red, b-sheets in yellow, and loops in green). The heme is represented in ball and sticks (C, O, N, and Fe atoms are in cyan, red, blue, and orange, respectively). CYP450 cycle In mitochondria, the second enzyme is ferredoxin and ferredoxin reductase. RH + O2 + NADPH + H+ ROH + H2O + NADP+ The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic  CYP oxidation reactions Hydroxylation (aliphatic or aromatic carbon) Epoxidation of double bond Heteroatom (S-, N- and I-) oxygenation Heteroatom (O-, S-, N-, Si-) dealkylation Oxidative group transfer , Cleavage of esters and Dehydrogenation Xenobiotic activation Cytochrome P450s biotransformation can lead to activation of some toxins and carcinogens. In some cases, the activation is desirable because it produces the active agent from a pro- drug. CYP Reactions Other CYP reactions: CYP450 enzymes can be induced or inhibited by many drugs and substances, resulting in drug interactions in which one drug enhances the toxicity or reduces the therapeutic effect of another drug Activation Of Acetaminophen  Examples of Common Drug-Drug Interactions Involving the Cytochrome P450 Enzyme System CYP Drug substrate Inhibitor inducer 1A2 Paracetamol, caffeine, tamoxifen, Theophylline Furafylline Smoking, charred foods 2A6 Coumarin, Caffeine Dicarb sodium 2C9 Diclofenac. Flubiprofen, losartan, phenytoin, Sulfapenazole Barbiturate, rifampicin Piroxicam, acid, Tolbutamide 2C19 Diazepam, (S) Mephenytoin, omeprazole, entamidine, Propranol (R) –Wafarin 26D Defuralol, codeine, haloperidol, nortriptyline Quinidine 2E1 Paracetamol, caffeine, chlozoxazone, theophylline Dicarb Sodium Alcohol, (ethanol) INH 3A4 Clarithromycin, dapsone, Indinavir, codeine, midazolam, Gastrodne Barbiturate, Rifampicin, cyclosporine, erythromycin, Nifedipine Felodipine, ketoconazole, dexamethasone, diazepam, verapamil, Loxatan, quinidine itraconazole carbamazepine Inhibition of CYP Inhibitors of CYP450s include: - Cimetidine, - Ciprofloxacin, - Erythromycin , - Fluoxetine Inhibition can lead to adverse drug reactions due to altered metabolism. It can be used to increase bioavailability of a drug, for example: - Ritonavir inhibits CYP3A enzymes. - Saquinavir is metabolised by CYP3A. - A combination of ritonavir and saquinavir is synergistic in HIV. Types of inhibition Inhibition can be due to a number of factors including: Competition for a CYP between two substrates Competition with a non-substrate inhibitor - Omeprazole and diazepam compete for CYP2C19. CYP2D6 metabolises dextromethorphan and is inhibited by quinine. Celecoxib inhibits CYP2D6. Grapefruit juice inhibits CYP3A enzymes. Substrates that can also be converted to a suicide inhibitor Erythromycin inhibits CYP3A4. Furafylline inhibits CYP1A2. Tienilic acid inhibits CYP2C9.  Terfenadine metabolism Terfenadine is a non-sedating H1 antagonist, It is metabolised to an active agent by CYP3A4. This active metabolite does not cross the blood-brain barrier (BBB). Azole antifungals and macrolide antibiotics inhibit CYP3A4, This results in increased plasma levels of terfenadine. Terfenadine blocks cardiac K+ channels, This can result in torsade de pointes and even ventricular arrhythmias.  Induction of CYP Some drugs can enhance the expression of some CYP enzymes. This can be beneficial because induction increases the pool of enzyme available to catalyse specific drug metabolising reactions. Making other drugs can be metabolised much more rapidly than would be anticipated. This does not cause a toxic effect but results in sub-therapeutic levels of drugs, such as oral contraceptives.  Mechanism of induction Cytosolic receptor mediated: - CYP1A and AhR (digoxin) - CYP2B and CARβ (phenobarbital) - CYP3A and PXR (rifampin) - CYP4A and PPARα (clofibric acid) Activation of the receptors leads to gene induction and increased mRNA production. Polymorphisms: Polymorphisms in the CYP family are considered to have the most impact on the fate of therapeutic drugs. Clinical relevance Phase II metabolism Phase II drug metabolising reactions are synthetic, anabolic reactions that involve conjugation whereby another molecule is added to the drug such as  Glucuronidation  Sulfation  Acetylation  Methylation  Glutathione conjugation  Amino acid conjugation These are primarily cytosolic reactions, and are much faster than Phase I reactions. Glucuronidation Glucuronidation: Glucuronidation is the most common Phase II reaction. - It is mediated by UDP-glycotransferases. - It requires uridine diphosphate-glucuronic acid as a co-factor. Substrates include: Aliphatic alcohols and phenols Carboxylic acids Secondary aromatic and aliphatic amines The resulting glucuronide conjugates of drugs are secreted in bile or urine depending on their molecular weight. Those of low molecular weight are excreted in urine whereas those molecules of high molecular weight are excreted in bile. It is a very important reaction, particularly for drugs such as: Acetaminophen ,Morphine, Propranolol, Diclofenac and Lamotrigine Sulfation Sulfation is described as a higher affinity but lower capacity reaction than glucuronidation. It has similar substrates to glucuronidation and is catalysed by sulfotransferases. The reaction requires the co-factor, 3’- phosphoadenosine-5’-phosphosulfate or PAP, which is the reason for the low capacity of this reaction, that is, the limitation of PAP. Sulfates The sulphate conjugates are excreted in the urine or bile. Sulfation can activate some carcinogens, such as safrole. Many drugs are sulfated: - Acetaminophen, - Chloramphenicol , - Dopamine and - Ethanol Methylation Methylation is a relatively minor reaction that often decreases water solubility. It is mediated by methyltransferases, with the best known being catechol-O-methyltransferase. The co-factor is S-adenosylmethionine. Methylated drugs include: Catecholamines Captopril Azathioprine N-acetylation N-acetylation is another major conjugation reaction, particularly for: Aromatic amines , Hydrazine It is mediated by N- acetyltransferases (NAT). The co-factor is acetyl-coenzyme A. This can also decrease water solubility. There are two enzymes involved, NAT1 and NAT2.  Slow acetylation NAT2 contains a number of polymorphisms that can decrease the rate of acetylation. Individuals who express this phenotype are known as slow acetylators. ~70% incidence in Middle East ~50% incidence in Caucasians 300 g/mol and with both polar and lipophilic groups are more likely to be excreted in bile. Smaller molecules are generally excreted only in negligible amounts. The molecular weight of most drugs is too low for efficient biliary excretion. Conjugation to glucuronic acid often increases molecular weight sufficiently for biliary excretion. Conjugation to acetate or glycine is generally too small. Bile is a significant route of excretion for: – Glucuronide conjugates (morphine) Pulmonary excretion Pulmonary excretion Pulmonary excretion refers to excretion through the lungs and breath. This is a significant route of excretion for some volatile molecules, especially anaesthetics. Excretion through the skin Excretion through the skin: sweat Drugs can be excreted through the skin. Drugs are secreted into sweat by passive diffusion. – This depends on the plasma/sweat partition coefficient (sweat pH: 4–6.8). There are also some active secretion mechanisms by which drugs can be excreted into sweat.  Excretion -Mammary  Most drugs administered to lactating women are detectable in breast milk. Fortunately, the concentration of drugs achieved in breast milk is usually low.  Infant would receive in a day is substantially less than what would be considered a “therapeutic dose.”  If the nursing mother must take medications and the drug is a relatively safe one, she should optimally take it 30–60 minutes after nursing and 3–4 hours before the next feeding.  Caution: Sedative-Hypnotics, Lithium Tetracyclines Excretion -Mammary Mammary: milk Mammary excretion is a minor route but can be clinically important. There is no active excretion, just passive diffusion. Concentration in milk reflects free concentration in blood. As milk is slightly acidic (with a pH of 7 compared to blood with a pH of 7.4), the ionisation of the drug may differ slightly between the milk and the blood — thus affecting its partitioning. Excretion -Mammary Erythromycin in milk: pH of breast milk: 7.0, pH of blood: 7.4 Drugs in milk: clinical significance The clinical relevance of the effect of a drug is evident when considering breastfeeding a baby, for example: – Tetracyclines are incorporated into teeth, which become weakened and 'mottled'. – Chloramphenicol can result in bone marrow toxicity and 'grey baby' syndrome, where babies cannot metabolise the drug effectively.  Saliva Excretion through saliva is a minor route but can be significant because of possible use in drug monitoring. Pharmacokinetic experiments often need a number of blood samples (10 or more) so there are doubts about ethical approval. Saliva sampling is non-invasive. For neutral molecules, salivary concentrations will reflect free concentrations in plasma. Ionised drugs are a problem. Saliva pH is variable so, in this case, there is a variable degree of ion trapping. Transmembrane passage Filtration Filtration is a passive process driven by pressure difference: Approximately 20% of plasma volume is filtered in one flow through the kidney. Small molecules with a molecular weight of less than 20,000 are readily filtered, including most drugs. Plasma albumin (Mwt: 68,000) cannot cross the membrane. Therefore, most proteins are not filtered nor are drugs that are extensively protein bound. Active secretion: Active secretion is energy dependent and transports substances from the plasma into the tubular urine. It can generate positive concentration gradients. Aside from specific transport systems, there are two relatively unspecific mechanisms, one for anions and one for cations (acids and bases). This process is saturable. Therefore, there are some possible interactions.  Actively Secreted Drugs Acids Cephaloridine Dopamine Frusemide Indomethacin Morphine Penicillins Pethidine Probenecid Quinine Thiazide diuretics Quaternary Ammonium salts for acid Probenecid and penicillins share the same mechanism secretion. Probenecid competes with penicillins – penicillin clearance is reduced.  Drug - Drug Interaction Drug interactions are changes in a drug's effects due to: Recent or concurrent use of another drug or drugs (drug-drug interactions) Ingestion of food (drug-nutrient interactions) Ingestion of dietary supplements (dietary supplement-drug interactions) Drug-drug interaction effects A drug-drug interaction may increase or decrease the effects of one or both drugs. Increased drug plasma levels can lead to a possible increase in toxicity and side-effects. Decreased plasma levels can lead to a possible decrease in efficacy and an increased risk of developing drug resistance. Clinically significant interactions are often predictable and usually undesired. Drug - Drug Interaction Two types of drug interactions : Pharmacokinetic (ADME) interactions & Pharmacodynamic interactions Pharmacokinetic interactions: A drug usually alters absorption, distribution, protein binding, metabolism, or excretion of another drug. Pharmacodynamic drug interactions: Pharmacodynamic drug interactions occur when one drug alters the sensitivity or responsiveness of tissues to another drug by: –Having the same effect (agonistic) –Blocking effect (antagonistic) These effects usually occur at the receptor level but may also occur intracellularly. Pharmacodynamic interactions You have reached the last tab. Ensure you have viewed all available tabs, and click Play to continue to the next slide.  Minimising interactions Clinicians should know all of their patients' current drugs. The fewest drugs in the lowest doses for the shortest possible time should be prescribed. Patients should be observed and monitored for adverse effects, particularly after a change in treatment. Effects that are influenced by enzyme induction may take more than one week to appear. Drug interactions should be considered as a possible cause of any unexpected problems. Prescribers should determine serum concentrations of selected drugs being taken, consult the literature or an expert in drug interactions and adjust the dosage until the desired effect is produced. If dosage adjustment is ineffective, the drug should be replaced by one that does not interact with other drugs being taken. Therapeutic effects Co-administration of the two anti-retroviral drugs, lopinavir and ritonavir, to patients with HIV infection results in altered metabolism of lopinavir and increased serum lopinavir concentrations and effectiveness. Lopinavir/Ritonavir is now marketed as a fixed dose combination drug for the treatment of HIV infection, combining lopinavir with a sub-therapeutic dose of ritonavir. Kaletra (high-income countries) and Aluvia (low-income countries) If fluoxetine is given with tramadol serotonin syndrom can result. This is a pharmacodynamic drug interaction. Fluoxetine and tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug Structure Activity Relationships (SAR) Structure Activity Relationships (SAR) SARs is the field of medicinal chemistry has evolved from an emphasis on the synthesis, isolation, and characterization of drugs to an increased awareness of the biochemistry of disease states and the design of drugs for the prevention of diseases. An important aspect of medicinal chemistry has been to establish a relationship between chemical structure and biological activity. An increased consideration in recent years has been to correlate the chemical structure with chemical reactivity or physical properties and these correlations can, in turn, be related to their therapeutic properties. Structure Activity Relationships (SAR) When a new type of active compound is discovered the chemist through alterations in its molecular structure, attempts to produce new compounds with similar, perhaps improved activity, or with other valuable active properties. At a given stage the effects observed are interpreted in terms of structural variations, which are then used to decide which modifications to consider next. Relating biological activities to molecular structures is known as structure-activity relationships (SAR). Aim of SAR Analyses SAR analyses try to convert structure-activity observations into informative structure-activity relationships. They aim at maximizing the knowledge that can be extracted from the raw data in molecular terms, exploit this knowledge to identify which molecules should be synthesized and identify lead compounds for either additional modifications or further pre-clinical studies. Results of a SAR Analysis The results of a SAR analysis can be represented in a condensed form, either in a ligand-based or a receptor- based approach, as illustrated below. They represent substantial amounts of time and money invested in human resources, scientific effort and human creativity in the project concerned. Structure Activity Relationships (SAR) These changes may be conveniently classified as changing: the size and shape of the carbon skeleton the nature and degree of substitution the stereochemistry of the lead Changing size and shape The shapes and sizes of molecules can be modified in a variety of ways, such as: changing the number of methylene groups in chains and rings increasing or decreasing the degree of unsaturation introducing or removing a ring system Structure Activity Relationships (SAR) Changing the number of methylene groups in chains and rings Increasing the number of methylene groups in a chain or ring increases the size and the lipophilicity of the compound. It is believed that any increase in activity with increase in the number of methylene groups is probably due to an increase in the lipid solubility of the analogue, which gives a better membrane penetration. Conversely, a decrease in activity with an increase in the number of methylene groups is attributed to a reduction in the water solubility of the analogues. This reduction in water solubility can result in the poor distribution of the analogue in the aqueous media as well as the trapping of the analogue in biological membranes. Structure Activity Relationships (SAR) Introducing chain branching, different sized rings and the substitution of chains for rings, and vice versa, may also have an effect on the potency and type of activity of analogues. For example, the replacement of the sulphur atom of the antipsychotic chlorpromazine by -CH2-CH2- produces the anti depressant clomipramine.  Structure Activity Relationships (SAR) Changing the degree of unsaturation The removal of double bonds increases the degree of flexibility of the molecule, which may make it easier for the analogue to fit into active and receptor sites by taking up a more suitable conformation. However, an increase in flexibility could also result in a change or loss of activity. The introduction of a double bond increases the rigidity of the structure. It may also introduce the complication of E and Z isomers, which could have quite different activities. The analogues produced by the introduction of unsaturated structures into a lead compound may exhibit different degrees of potency or different types of activities. Structure Activity Relationships (SAR) For example, the potency of prednisone is about 30 times greater than that of its parent compound cortisol, which does not have a 1–2 C=C bond. The replacement of the S atom of the antipsychotic phenothiazine drugs by a – CH=CH- group gives the antidepressant dibenzazepine drugs, such as protriptyline. Structure Activity Relationships (SAR) The introduction of a C=C group will often give analogues that are more sensitive to metabolic oxidation. This may or may not be a desirable feature for the new drug. Furthermore, the reactivity of the C=C frequently causes the analogue to be more toxic than the lead. Structure Activity Relationships (SAR) Introduction or removal of a ring systeme The introduction of a ring system changes the shape and increases the overall size of the analogue. The effect of these changes on the potency and activity of the analogue is not generally predictable. However, the increase in size can be useful in filling a hydrophobic pocket in a target site, which might strengthen the binding of the drug to the target. Structure Activity Relationships (SAR) For example, it has been postulated that the increased inhibitory activity of the cyclopentyl analogue (rolipram) of 3-(3,4- dimethyloxyphenyl)- butyrolactam towards cAMP phosphodiesterase is due to the cyclopentyl group filling a hydrophobic pocket in the active site of this enzyme. Principle: Alteration of an Active Substance The progressive alteration of the molecular structure of a reference compound allows for the determination of the importance of the structural elements involved. This can be done by removing, adding or replacing specific molecular fragments and testing how the structural variation affects biological activities. For example, if the analog is inactive, the original functional group is interpreted as being essential to binding; if the activity is not affected, the original functional group is considered to be unimportant. Each of the novel molecules synthesized is expected to yield useful knowledge. Development: a Single Modification at a Time Data of high informational content can be obtained when derived from single structural modifications of an initial lead structure. The introduction of multiple changes should be avoided because of the difficulties created for the correct interpretation of the biological results. The example below illustrates a molecule for which three alterations were introduced. In the absence of other SAR, the interpretation of the inactivity of the resulting molecule is impossible. Applications of SAR Pharmacokinetic studies The pharmacokinetic approach entails studying the four steps of absorption, distribution, metabolism, and excretion (ADME) of a certain drug. The bioavailability of a drug is based on the absorption and metabolism of a compound. The absorption depends on the solubility and lipophilicity and can be modified by the addition of alcoholic, acidic, or carboxylic groups. The high rate of metabolism, on the other hand, can reduce bioavailability. SAR can be used to determine the solubility, rate of reaction, metabolism, and other factors between drugs. Applications of SAR Drug-receptor interaction The interaction between drugs and receptors occurs by reversible binding where weak ionic bonds may form between the drug and receptor. Another method is irreversible binding, as in the case of covalent bonds. SAR can be determined using various in silico methods that have been developed to understand the interaction between target receptors and drugs. Applications of SAR Modification of drugs SAR method is extensively used to optimize and develop various types of drugs. The in silico methods developed using SAR include the statistical method, quantum analysis, artificial network modeling, validation method, etc. Applications of SAR Toxicity studies The toxicity of a drug is critically linked to its dose. If the dosage of a drug is too high, it can cause toxicity, and if it is too low, it can lead to no or less activity. Thus, the minimum effective concentration of a drug is a rather important property, and this parameter can also be determined using SAR. Also, the lack of specificity of a drug can also lead to side- effects. Applications of SAR Formulation of chemical and physical properties SAR has emerged as a great tool to understand and develop the chemical and physical properties of drugs. The structural information accorded by SAR can help in designing an organized approach to creating drugs that have desired potency and specificity.  References 1. Dawes M, Chowienczyk PJ. Pharmacokinetics in pregnancy. Best Practice & Research Clinical Obstetrics and Gynaecology. Vol. 15, No. 6, pp. 819±826, 2001. doi: 10.1053/beog.2001.0231, available online at http://www.idealibrary.com. 2. Further Reading: Loebstein R, Lalkin A & Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clinical Pharmacokinetics 1999; 33: 328±343. 826 M. Dawes and P. J. Chowienczyk 3. Hibernia College Dublin Ireland: Clinical Pharmacology and the Role of Pharmacometrics, ADMEL 2014 CPD Lecture Series 4.Penta, S. (2016). Introduction to Coumarin and SAR Advances in Structure and Activity Relationship of Coumarin Derivatives. www.elsevier.com/.../978-0-12-803797-3. 5. Bian, et al. (2018) Exploring the Structure-Activity Relationship and Mechanism of a Chromene Scaffold (CXL Series) for Its Selective Antiproliferative Activity toward Multidrug- Resistant Cancer Cells. ACS Publications. https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00813 6. McKinney, et al. (2000) The Practice of Structure-Activity Relationships (SAR) in Toxicology. Toxicological Principles. https://academic.oup.com/toxsci/article/56/1/8/1646041.