FTM LECTURE 30 - PHARMACODYNAMICS PDF

BPM1 PHARMACOLOGY Spring Term 2024 PHARMACODYNAMIC DR TAREK ALMABROUK Lecture Objectives ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0001 Define the following terms: drug, pharmacology, pharmacodynamics, pharmacokinetics, pharmacotherapy and toxicology. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0002 Define drug receptor and list...

BPM1 PHARMACOLOGY Spring Term 2024 PHARMACODYNAMIC DR TAREK ALMABROUK Lecture Objectives ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0001 Define the following terms: drug, pharmacology, pharmacodynamics, pharmacokinetics, pharmacotherapy and toxicology. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0002 Define drug receptor and list the different classes of receptors with which drugs interact. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0003 Give examples of drugs whose actions are not mediated by binding to receptors. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0004 Describe and interpret graded dose-response curves. Define Emax and EC50. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0005 Describe and interpret drug-receptor binding curves. Define KD and Bmax. Define affinity. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0006 Define spare receptors and signal amplification. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0007 Compare and contrast in vitro experiments with whole animal experiments. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0008 Define efficacy and potency. Indicate the positions on a graded dose-response curve that are used to define drug potency and efficacy. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0009 Define agonist, antagonist, full agonist, partial agonist, and inverse agonist. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0010 Describe the different mechanisms of receptor and nonreceptor antagonism. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0011 Describe and interpret quantal dose-response curves. Define ED50, TD50 and LD50. ▪ SOM.1ai.BPM1.1.FTM.4.PHAR.0012 Explain therapeutic index and therapeutic window. A Few Definitions ▪ Drug: any substance that, when administered to a living organism, produces a biological effect. ▪ Pharmacology: the study of how the function of living systems is affected by chemical agents. ▪ Clinical pharmacology or Pharmacotherapeutics: the study of the use of drugs in the prevention and treatment of disease. ▪ Pharmacotherapy: use of drugs to treat disease. ▪ Toxicology: the study of adverse effects of drugs. Divisions Pharmacokinetic Pharmacodynamic The study of Absorption, Distribution, Metabolism and Excretion of drugs (ADME). The study of the effects of drugs and their mechanisms of action. What the body does to the drug? What the drug does to the body? Pharmacokinetics & Pharmacodynamics SOM.1ai.BPM1.1.FTM.4.PHAR.0001 5 Mechanisms of Drug Action Drug Drugs are chemicals that alter basic processes in body cells. They can stimulate or inhibit normal cellular functions. To initiate a cellular response, a drug must first bind to a drug receptor. In most cases, drugs bind to their receptor by forming hydrogen, ionic, or hydrophobic bonds with the receptor. These weak bonds are reversible. In a few cases, drugs form covalent bonds with their receptor. This strong bonds are irreversible. Drug-Receptor complex Target cell Receptor Pharmacologic effect Mechanisms of Drug Action (Selectivity) Drug receptors are responsible for the selectivity of drug action. The size, shape, and charge of a drug determine whether it will bind to a particular receptor or set of receptors. For a drug to be useful as a therapeutic tool it must act selectively on particular types of receptors, ie, it must show a high degree of binding selectivity. The majority of drug receptors are physiological receptors, which mediate the actions of neurotransmitters and hormones. Other classes of proteins, such as enzymes, transport proteins, and structural proteins are also drug receptors. SOM.1ai.BPM1.1.FTM.4.PHAR.0002 9 Mechanisms of Drug Action Receptor-Mediated Mechanisms (Binding with biomolecules) Drugs can produce their actions by binding with biomolecules ( Protein Targets ). Targets are mostly protein in nature Protein targets for drug binding : G-protein-linked receptors Enzyme-linked receptors Ion Channels Nuclear receptors Enzymes Transporters Structural proteins Non-Receptor-Mediated Mechanisms Involve biological processes without direct interaction between a signalling molecule and a cellular receptor. The interaction could be: Physical Chemical G-Protein Coupled Receptors Approximately 60 % of prescription drugs act by binding to G protein-linked receptors. Located at cell membrane. Coupled to intracellular effectors via G-protein. Response through ion channels or enzymes. (not direct) Involved in rapid transduction. So, the Response occurs in seconds. Has different classes of receptors: Cholinergic R (Ach) Adrenergic R (NA) Examples: Albuterol, a β2-agonist, is used for asthma. Propranolol, a β-antagonist, is used for hypertension. Enzyme-Linked Receptors The largest group is the receptor tyrosine kinase family. Located at the cell membrane. Linked to an enzyme (with intrinsic enzymatic activity). Response occurs in minutes to hours. Involved in response to hormones and growth factors. They control many cellular functions as metabolism and growth Has different classes of receptors: Insulin receptor Epidermal growth factor receptor (EGFR) Examples: Insulin Enzyme-Linked Receptors Tyrosine kinase receptors play an essential role in cellular growth and differentiation. Gain-of-function mutations in these receptors can lead to cancer. Inhibitors of tyrosine kinase receptors are used as anticancer agents. An example is imatinib, which is effective for leukaemia. Ion Channels Located at the cell membrane. Directly activated by ligand binding. (no second messenger needed) Directly related to ion channels. (when the drug starts producing its effect, the effect will directly change the ion channel, open or close the channel). Response occurs in milliseconds. Involved in very fast synaptic transmission. Has different classes of receptors: Nicotinic receptors GABA Examples: Local anesthetics Sedative-hypnotics Antiepileptics Nuclear Receptors Located intracellularly. Directly related to DNA (Gene transcription). Activation of receptors either increase or decrease protein synthesis. Response occurs in hours or days and persists longer. Has different classes of receptors: Estrogen Steroid Examples: Steroid hormones Thyroid hormone Vitamin D Enzyme Response occurs in minutes to hours. Most drugs that target enzymes act by inhibiting enzyme activity. Has different classes of Target: cyclooxygenase (COX) enzyme H+,K(+)-ATPase Examples: Aspirin Ibuprofen Omeprazole Transporters It is responsible for transporting ions and small organic molecules between intracellular compartments, through cell membranes, or in extracellular fluids. Drugs bind to such molecules to alter their transport ability. Most drugs that target enzymes act by inhibiting enzyme activity. For example, neurotransmitter transporters are targets of drugs used in the treatment of psychiatric disorders. Has different classes of Target: Dopamine transporter Noradrinaline transporter Serotonine transporter Examples:  Prozac (Fluoxetine) Antidepressant Structural Proteins Some anticancer drugs bind to tubulin and prevent the polymerisation of this molecule into microtubules. As a consequence, cells are arrested in metaphase. Has different classes of Target: Tubulin Examples: Vinblastine Colchicine Non-Receptor Mediated mechanism Some drugs do not act by interacting with macromolecular components of the organism. Drugs can produce actions by: Chemical actions: Neutralization of gastric acidity by antacids. Or physical actions: interference with absorption. Has different classes of Targets: Antacids Chelating Laxative Examples: Calcium carbonate penicillamine Senna Dose-Response Curves Dose-Response Curves There are two major types of dose-response relationships: graded and quantal. When the response of a particular receptor is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration is called a graded dose-response curve. A quantal dose-response curve represents the relationship between the dose of a drug and the proportion of a population that shows a specified response to that dose, rather than the magnitude of the response. Quantal dose-response data is often presented in a binary fashion (e.g., response or no response). Graded Dose-Response Curve It is a correlation between drug concentration used (x- axis) and drug response (y-axis ) The relation between drug concentration and effect is described by a hyperbolic curve according to the following equation: Emax x C E= ⎯⎯⎯⎯⎯ C + EC50 E is the effect. Emax is the maximal response produced by the drug. EC50 is the drug concentration that produces 50% of the maximal effect. Graded Dose-Response Curves Emax 100 % Effect 50 EC50 0 SOM.1ai.BPM1.1.FTM.4.PHAR.0004 5 10 Drug Concentration 15 20 28 Receptor Binding of Drugs The relation between drug bound (B) to receptors and the concentration (C) of free drug is described by the equation: Bmax x C B= ⎯⎯⎯⎯⎯ C + KD Bmax is the total concentration of receptor sites. KD is the equilibrium dissociation constant. KD is the concentration of drug required to occupy half of the receptors. KD characterises the receptor’s affinity for the drug. Affinity is the tendency of a drug to combine with its receptor; it is a measure of the strength of the drug-receptor complex If KD is low, binding affinity is high, and vice versa. Receptor Binding of Drugs Bmax 100 % Receptors bound 50 KD 0 SOM.1ai.BPM1.1.FTM.4.PHAR.0005 5 10 15 Drug Concentration 20 31 Binding Curve & Dose Response Curve The shape of the dose-response curve is similar to the binding curve because the response to the drug is a consequence of the binding of the drug to the receptor Graded Dose-Response Curves ▪ Dose-response data is frequently plotted as the drug effect against the logarithm of the concentration. This transforms the hyperbolic curve into a sigmoid curve. Summary: Spare Receptors & Signal Amplification An agonist does not have to occupy all receptors to evoke a full response. Therefore, EC50 is lower than KD. Because of this a certain number of receptors are said to be "spare." The presence of spare receptors indicates that there is signal amplification. Spare Receptors & Signal Amplification Example EPINEPHRINE Spare Receptors & Signal Amplification Dose-Response Curve Invitro vs Whole animal Experiment In population in vitro in vivo (whole Animal) Efficacy & Potency Efficacy Efficacy is the magnitude of the response a drug produces. Maximal efficacy (sometimes referred to simply as efficacy), is the greatest effect a drug can produce (Emax). SOM.1ai.BPM1.1.FTM.4.PHAR.0008 Potency Potency is a measure of the concentration or amount of drug necessary to produce an effect of a given magnitude. The EC50 of a drug is usually used to determine potency. The potency of a drug depends both on the affinity and the efficacy of the drug. 40 Efficacy & Potency Efficacy & Potency ▪ Drug A is more potent than Drug B. Emax Emax % Response A B 50% C 5 10 15 20 EC50 EC50 EC50 Emax ▪ Drug A and Drug B have equal efficacy. ▪ Drug C has lower potency and lower efficacy than Drugs A and B. Log Drug concentration SOM.1ai.BPM1.1.FTM.4.PHAR.0008 42 More about Efficacy & Potency A and B are antihypertensive drugs. At low responses A is more potent than B. At high responses B is more potent than A. Therefore, no comparisons can be made between A and B in terms of potency because the Emax are different. Type of Receptors Interaction AGONIST AND ANTAGONIST Types of Drug-Receptor interaction It is a drug that combines with the receptor and elicit a response Agonist Full Agonist Antagonist Partial Agonist Is a drug that combines with the receptor without producing a response. It blocks the action of the agonist. A drug that combines with its Combines with its receptor and evokes a specific receptor to produce response that’s a submaximal effect maximal effect by increasing regardless of its concentration its concentration MECHANISMS OF DRUG ANTAGONISM Classification of Antagonism SOM.1ai.BPM1.1.FTM.4.PHAR.0010 47 RECEPTOR ANTAGONISM (General Features) A receptor antagonist binds to the same receptor to which the agonist binds. Receptor antagonists bind to receptors but do not activate them Receptor antagonists have affinity but NO efficacy. They inhibit the action of an agonist but have no effect in the absence of the agonist. Agonists have receptor affinity and efficacy. Receptor antagonism can be competitive or noncompetitive. Competitive Antagonism Competitive antagonists bind to the same agonist binding site on the receptor. Binding of antagonist to the agonist binding site prevents the binding of agonist to the receptor. Binding of antagonist to the receptor may be reversible or irreversible. Reversible Competitive Antagonism It binds to the same site on the receptor as an agonist. Increasing the concentrations of agonist can surmount the effect of a given concentration of the antagonist. the efficacy (Emax) for the agonist remains the same (i.e., Inhibition is reversible). The presence of the reversible competitive antagonist increases the concentration of agonist required for a given degree of response. So, the agonist concentration-effect curve shifts to the right ( parallel) and the potency of the agonist is decreased. Many clinically used drugs belong to this class. Emax Emax 100 % Effect Agonist alone Agonist + reversible competitive antagonist 50 0 EC50 EC50 Log [Agonist] No change in the Efficacy (Emax). D-R curve shifts to the right. EC50increased. Therefore, Potency is reduced. Irreversible Competitive Antagonism Some authors refer to this type of antagonism as noncompetitive. It binds to the same site on receptor as agonist. A receptor bound by an irreversible antagonist cannot respond to the binding of an agonist. inhibition cannot be overcome by increasing agonist concentration (i.e., inhibition is irreversible, Insurmountable) The Emax of the agonist is reduced. Emax 100 % Effect Efficacy (Emax) Decreased. D-R curve shifts downward. Agonist alone 50 Emax Agonist + irreversible competitive antagonist 0 EC50 Log [Agonist] Noncompetitive Antagonism Also called allosteric antagonism. Noncompetitive antagonists bind to the receptor at a site different from the agonist binding site. This type of antagonism is insurmountable. Emax is decreased. Emax 100 % Effect Efficacy (Emax) Decreased. D-R curve shifts downward. Agonist alone 50 Emax Agonist + non-competitive antagonist 0 EC50 Log [Agonist] Irreversible Competitive Antagonism & Noncompetitive Antagonism NONRECEPTOR ANTAGONISM ▪ A nonreceptor antagonist does not bind to the receptor to which the agonist binds. Nonreceptor antagonism Physiological antagonism Chemical antagonism Functional (physiological) antagonist Functional (physiological) antagonist: In this type of antagonism, two different molecules working through separate receptors produce physiologically opposite effects. Chemical Antagonism A chemical antagonist reacts chemically with an agonist to form an inactive product. For example, protamine, a protein which is positively charged, counteracts the effects of heparin, an anticoagulant that is negatively charged. Full & Partial Agonists Agonists activate the receptor that they occupy. Antagonists cause no activation. But the ability of a drug molecule to activate the receptor is a graded property. Full agonists produce a maximal response. Partial agonists produce a submaximal response. Partial agonists produce a lower response, at full receptor occupancy, than do full agonists. Full & Partial Agonists 100 Full Agonist Partial agonist 50 0 Log [Drug] Partial agonist acts as Competitive antagonist A partial agonist can compete with and displace a true agonist from a receptor and thus act as an antagonist in certain situations; e.g., tolazoline, which is used to treat painful peripheral vasospasm, is a partial agonist at α1 receptors (α1 agonists cause peripheral vasoconstriction). Partial agonist Log [Drug] % Effect % Effect Full Agonist Full agonist alone Full agonist + partial agonist Log [Full agonist] Inverse Agonists Many receptor systems exhibit some activity in the absence of an agonist, suggesting that a fraction of the receptors is always in the active state. Activity in the absence of an agonist is called constitutive activity. Inverse agonists reverse the constitutive activity of a receptor. Inverse agonist: Binds to the receptor as an agonist, but not to the same active site. It elicits a response that is opposite to the agonistic response and has a negative efficacy. 67 Effect of various types of ligands on receptor responses https://en.wikipedia.org/wiki/Inverse_agonist Quantal Dose-effect Curves The quantal dose–response relationship plots the fraction of the population that responds to a given dose of drug as a function of the drug dose. The responses are defined as either present or not present (i.e., quantal, not graded), such as prevention of convulsions, arrhythmia, or death. Quantal Dose-effect Curves Uses: Median Effective Dose (ED 50): 01 Median Toxic Dose (TD 50): 02 is a dose of the drug required to produce a therapeutic effect in 50% of individuals. Dose = concentration 03 Median Lethal Dose (LD 50): is the dose of a drug required to produce death in 50 % of individuals. is the dose of a drug required to produce toxic effects in 50 % of individuals. The clinical trials done on animals only 04 Therapeutic index (TI) Quantal Dose-effect Curves Relationship between dose of phenobarbital and protection of rats against convulsions. Relationship between dose of phenobarbital and its lethal effects in rats. Therapeutic Index The therapeutic index is defined as the ratio of the TD50 or the LD50 to the ED50 for a therapeutically relevant effect. TD50 TI = ⎯⎯⎯ ED50 Or LD50 TI = ⎯⎯⎯ ED50 72 Therapeutic Index The therapeutic index of a drug in humans is almost never known with real precision. The TI represents an estimate of the safety of the drug. A very safe drug will have a very large toxic dose and a small effective dose. Very safe drug will have very wide therapeutic index. 73 The Therapeutic Window The therapeutic window is a more clinically relevant index of safety. It is the dosage range between the minimum effective therapeutic concentration (MEC) and the minimum toxic concentration (MTC). The Therapeutic Window THE END