RXRS-302 Finals Study Guide (Cumulative) PDF

Week 1: Basic Principles of Pharmacology Pharmacology is the understanding and science of drug and drug-mediated actions on a biological system: 1. Includes the mechanism of action leading to therapeutic and/or toxic actions 2. May include the dosage or concentration achieved in the blood and the de...

Week 1: Basic Principles of Pharmacology Pharmacology is the understanding and science of drug and drug-mediated actions on a biological system: 1. Includes the mechanism of action leading to therapeutic and/or toxic actions 2. May include the dosage or concentration achieved in the blood and the desired tissue Pharmaceutical science is a related field that focuses on the physical and chemical properties of the pharmacologic agent. A drug is a chemical or biological substance that interacts with its target (e.g. enzyme, receptor), where its binding produces a physiological effect—regardless of whether the effect is beneficial. Any chemical (e.g small molecule, polymer, or biological agent), where its binding onto the target can alter the biological properties and/or biochemistry of a living organism. The beginning of pharmacognosy and pharmacology: Since the beginning of antiquities, man used natural resources to develop remedies to resolve or ameliorate various ailments. ○ E.g pulverized leaves mixed with mud and cool water used to stop bleeding. The transformation from pharmacognosy to chemicals: ○ Conversion of mixtures and powders into modern pharmacology began with the introduction of animal experimentation and isolation of active pharmaceutical ingredients. Individualizing therapy: Primary disease (e.g phenotype of the causative agent): understanding characteristics of the disease to appropriate treatment approach. Considerations for co-morbid states: refers to the presence of additional medical conditions alongside the primary disease. Conditions can influence the choice of medications. Impact of concomitant drugs that are being administered: consideration of any medications that patient is currently taking. Age/patient of patients: pediatric and geriatric patients typically require lower doses. Pharmacogenetics: involves studying how an individual’s genetic makeup affects their response to medications. E.g drug metabolism. Renal and hepatic status: the function of kidneys and liver play a vital role in drug metabolism and elimination. Disciplines in pharmaceutical sciences: Pharmacology: study of drug actions on a biological system Pharmacognosy: science in identifying the active ingredient from a plant-based source. Pharmaceutical science: The science of understanding the physical and chemical nature of the drug product. Pharmacy: Science of identification, selection, preservation, standardization, compounding and dispensing of medical substances. Therapeutics: science relating to the effective treatment or relief of symptoms. Toxicology: Study of adverse events associated with a dosage or concentration in a biological system. Development of methods and treatment of adverse events. Drug binding and types of responses: Drug binding to a receptor/target is mediated by the chemical properties/structure of the compound that dictates interaction with complementary surfaces found on the receptor/target. ○ Agonists: activate cellular signaling pathways to alter physiologic activity ○ Antagonists: bind to the receptor/target but cannot initiate a change in cellular function. Occupation of the receptor without activation results in blockade of the actions of agonists. ○ Partial antagonists: are compounds that bind to and activate a given receptor target but have only partial activation at the targeted site relative to a full agonist. Types of drug-mediated effects: Therapeutic: desired physiological effect mediated by the pharmacologic interaction with the target. This is normally an expected or predictable physiological response induced by the drug. Side effect: this is the unintended or secondary physiological effects mediated by a drug at the therapeutic dosages or concentrations. These effects can be beneficial or toxic. Adverse effect: undesired physiological effect associated with a drug or its byproduct. Oftentimes this can have harmful effects/ Toxic effects: are produced where levels of the parental drug or its metabolites cause harmful effects. This is often caused by impaired clearance (renal or metabolic) which allows the drug or its metabolites to accumulate. Cellular Receptors and Enzymes: Cell surface or intracellular regulatory proteins — mediate the effects of endogenous chemical signals such as neurotransmitters and hormones. E.g adrenoreceptors, steroid receptors, and acetylcholine receptors. Enzymes — cell surface, membrane-spanning or intracellular proteins inhibited (or less commonly activated) by the binding of a drug. E.g Na+/K+ ATPase is the cell surface receptor for cardiac glycosides such as digitals. Structural proteins — extra or intracellular proteins inhibited (or less commonly activated) by the binding of a drug. E.g tubulin is the receptor for colchicine, an anti-inflammatory agent. Types of Cellular Responses: Plasma membrane bound receptors (agonist): ○ Na pump which leads to an activator of conductance. ○ G-protein activation, generation of second messenger, activation of cell signaling. Intracellular receptors: ○ Phosphorylation of tyrosines on key signaling molecules, activation of cell signaling. ○ Transport to nucleus, activation of transcription and translation. Membrane bound receptors: Ligand-regulated transmembrane enzymes e.g. protein tyrosine kinase receptor Polypeptides that cross the plasma membrane consist of an extracellular hormone binding domain and a cytoplasmic enzyme domain. The enzymatic domain may be tyrosine or serine kinase or guanylyl cyclase. Examples of endogenous substances that utilize tyrosine kinase receptors are: insulin, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). Plasma-Membrane Bound Receptors: Ligand gated channel receptors: ○ These receptors transmit their signals by increasing the flow of relevant ions and altering the electrical potential across the membrane. ○ Examples of transmitters include acetylcholine, GABA and the excitatory amino acids (e.g Glutamate, aspartate). ○ Time between the binding and response can be measured in milliseconds. The rapidity of this signaling mechanism provides rapid information transfer across the synapse. Binding and Receptor Activation: Drug A (agonist) + Receptor ⇔ Drug A agonist + Receptor ⇔ AR …. Response Occupation governed by affinity | Activation governed by efficacy Drug B (antagonist) + Receptor ⇔ Drug B antagonist + Receptor …. No Response Drug Dosage and Effect Relationship: Dose at which 50% of maximal effect is observed is referred to as the ED50. Clinically, the relationship may be quite complex. However, in carefully controlled vitro systems, the relationship between drug concentration and its effect is often simple and may be described with mathematical precision. Effect = Effectmax[Drug]/EC50 + [Drug] Factors Governing Drug Actions: Affinity is a measure of the tightness with which a drug binds to the receptor. Intrinsic activity is a measure of the ability of an agonist that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity. Maximal Drug Response and Spare Receptors: As the concentration of a drug in a human organ system increases, the response of that system would be expected to increase until a maximal response is obtained. The relationship between the number of receptors occupied and the physiologic response is c complex. In many human physiological systems, not all receptors must be occupied by drug to achieve a maximal response. A certain number of receptors are “spare”. Drug Potency and Efficacy: Potency refers to the concentration of a drug required to produce a given physiological effect. Drugs with high receptor affinity will exhibit greater potency than those with lower affinity. Efficacy is often used to describe the maximal level of response a drug can produce. Drug A and B have the same efficacy, drug A has greater potency than B or C because the dose of B and C must be larger to produce the same effect as A. Although Drug C has a lower efficacy than B, it is more potent than B at lower drug concentrations. Agonist Dose-Response Curve sin the Presence of Antagonists: Allosteric Regulation: Allosteric inhibitors induce a conformational change that changes the shape of the active site and reduces the affinity of the recepto’s active site for its substrate. Allosteric activators induce a conformational change that changes the shape of the active site and increase the affinity of the receptor’s active site for its substrate Route of Administration: Considerations for Dosage Forms: Active pharmaceutical ingredient: ○ Small molecule, small peptide, macromolecule, cellular therapeutics Pharmaceutical Dosage Form ○ Basic Dosage Form: Gastrointestinal: Oral, Per rectal (PR), sublingual, buccal Inhalation: intranasal, intrapulmonary Parenteral: intravenous, intramuscular, subcutaneous Dermal: transdermal, ointment or cream Formulation Consideration: ○ Route of administration, release characteristics, biotransformation, intended targeted sites. Dosage Route Consideration: Systemic Administration: ○ Advantage: able to provide drug concentrations that will be able to manage systemic conditions. The dosage and concentration required for physiological effects. ○ Disadvantages: The potency for off-target activity. Potential for unintended toxicities. Regional Administration: ○ Advantage: Avoids unintended dosing to unaffected sites, reduce systemic toxicities ○ Disadvantages: increase incidence of local toxicities, potentially affect localized tissues due to high concentration of the compound at the administered sites. Patient Considerations: Prescribers assess characteristics to determine route of administration. Some patients are unable to swallow: ○ Very young or older adult patients might have difficulty swallowing. ○ Avoid solid, oral dose forms in favor of liquid dose forms or non oral routes of administration ○ Oral route of administration is inadvisable for a patient experiencing nausea and vomiting. Overview of Absorption and Elimination: Xenobiotic Absorption: ○ Orally administered drugs are absorbed largely from the small intestine to large intestines. (some intranasal, sublingual, rectal absorption via suppository, inhaled and rarely absorption from stomach). ○ Molecules need to be near the mucosa layer to be absorbed. Compounds should be soluble in fut contents or in vehicle ○ Crystals are not well absorbed. ○ Cummy stuff is not well absorbed. Anatomy of the Intestines and Types of Absorption: The intestines are a long, continuous tube of mucosal cells running from the stomach to the anus. Most absorption of nutrients and water occurs in the intestines. The intestines include the small intestine, large intestine, and rectum The small intestine (small bowel) is ~20 feet long and about an inch in diameter ○ It absorbs most of the nutrients from what we consume. ○ Velvety tissue lines the small intestine, which is divided into the duodenum, jejunum and ileum. The large intestine (colon or large bowel) is about 5 feet long and about 3 inches in diameter. ○ The colon absorbs water from wastes, creating stool, as stool enters the rectum, nerves there create the urge to defecate. Vasculature of the Intestines: Drug-like nutrients are absorbed through the intestinal walls and enter into the bloodstream (red: arteries, blue: veins). There are protective mechanisms to prevent the entry of undesirable compounds or agents. The gastrointestinal system has both responses to xenobiotics and immunity to protect from pathogenic intrusion. Overall Transport Across Membrane: Once a drug/xenobiotic has been systemically, it can circulate into various organs. Free drug can be transported across membranes and into tissue Extracellular drugs can then enter into cells and exert their activities in the targets Free drug are also susceptible to elimination and metabolism Site of Action: Choice of route of administration is influenced by the desired site of action. The term ‘local use’ refers to site-specific applications of drugs. The term systemic use refers to the application of a drug to the site of action by absorption into the blood and subsequent transportation throughout the body. Even drugs meant for systemic administration are usually targeted to a specific site of action. Factors Influencing The Route of Administration: A route of administration is a way of getting a drug onto or into the body. Drugs come in many different forms: ○ Designed by pharmaceutical scientists for administration or application ○ Many factors determine the choice route of administration. Onset of Action: Sublingual or buccal tablets or film placed under tongue or between cheek and gums work quickly medication bypasses stomach and liver, goes directly into bloodstream Drugs injected/infused directly into bloodstream are carried immediately throughout the body Topical medications work quickly: ○ Localized therapeutic effects: applied to the skin, inhaled into the lungs, instilled into the eye. Duration of Action: The duration of action is the length of time a drug gives the desired response or is at the therapeutic level. Controlled/extended-release tablets may last for 12-24 hours compared with 4 to 6 hours for the same drug in immediate-release formulation. Transdermal patches deliver small amounts of a drug steadily over many hours or even days. Sustained duration effect can be achieved by means of intravenous infusion Injections into the muscle and skin last longer than injections directly into the bloodstream. Types of Dosage Forms: Oral Dosage Form: tablets, capsules, liquids, solutions, suspensions, syrups, elixirs, sublingual, buccal, sublingual strips. Non-oral dosage forms: intravenous, subcutaneous, intravitreal, topical: dermal, inhale, rectal. Oral Delivery Forms: Advantages: ○ Ease and safety of administration ○ Active ingredient is generally contained in powders or granules which dissolve in the GI tract. ○ Sublingual and buccal administration has a rapid onset (less than 5 min). Disadvantages: ○ Delayed onset dose form must disintegrate before absorption ○ Destruction or dilution of drug by GI fluids food or drink in stomach or intestines ○ Not indicated in patients who have nausea or vomiting are comatose, sedated, or otherwise unable to swallow. ○ Unpleasant taste of some liquid dose forms must be based on flavorings to promote compliance. Design of Drug Products: Effectiveness, safety, reliability, stability: (physical, chemical, microbiological), pharmaceutical elegance (appearance, organoleptic properties), convenience (ease of use, dosing frequency, consumer acceptance). Buccal Sublingual Administration: Avoid first pass effects, rapid onset of action, deliver drugs well pass the BBB, can only deliver small dosages, may have adverse taste issues. Advantages and disadvantages of the parenteral route: The intradermal (ID) route of administration is used for diagnostic and allergy skin testing ○ Patients may experience a severe local reaction if allergic or has prior exposure to a testing antigen. Dispensing and administering parenteral medications Most parenteral preparations are made up of ingredients in a sterile-water medium ○ The body is primarily an aqueous (water-containing)) vehicle Parenteral preparations are usually: solutions or suspensions. Parenteral Medications: IV injections and infusions are introduced directly into the bloodstream ○ Must be free of air bubbles and particulate matter ○ Introduction of air particles might cause embolism, blockage in a vessel, or severe painful reaction at the injection site. ○ Fast acing route because he drug goes directly into the bloodstream ○ Often used in the emergency department and in critical care reas ○ The solution must be sterile in its prepackaging ○ Commonly used for fluid and electrolyte replacement to provide necessary nutrition to the patient who is critically ill ○ The API must be stable and soluble in aqueous fluid Topically Administered Drugs: Drugs are applied in the form of ointments, pastes, poultice and cream to the skin for their local action. However, absorption through skin can be increased by suspending the drug in an oily vehicle and rubbing the preparation into the skin. This method of administration is called inunction. Drugs applied locally on the skin are poorly absorbed through the epidermis. Permeabilization of dermis is permeable and can enhance systemic absorption of drugs. Abraded, burned or denuded skin can either enhance or decrease drug absorption across the dermis. Inflammation and other conditions that enhance cutaneous blood flow also promote absorption Transdermal Drug Delivery Systems: Drug is placed in a reservoir and crosses the dermis using concentration gradients going from high to lower concentration. The amount of drug being transported can be modulated by skin temperature as compared to the reservoirs. Advantages and disadvantages of SL and Buccal: Sublingual and buccal administration has a short duration of action, less than 30-60 minutes. Buccal route may have medicinal taste Potential local mouth irritation. Inhaled Therapeutics: Inhalation or pulmonary absorption—gaseous compounds/drugs may be inhaled Drugs are absorbed across the mucous membrane of the respiratory tract and through pulmonary endothelium and ultimately reach the circulation. Absorption can be rapid Volatile or gaseous anesthetics such as halothane, enflurane, and nitrous oxide are administered by this route. Inhaled bronchodilators or steroids are generally given via inhalers in aerosol form Inhalers can provide an accurately metered doses of drugs to be delivered into various parts of the lung through size and velocity of the particles This development has greatly extended the scope of this technique. Impact of Age on Aerosolized Delivery: Delivery to the site is dependent on the diameter of the particle. Age is a determining factor. The type of devices used will also impact the ability to deliver the drug to the alveolar. Intravitreal Injections: The route of choice for treating retinal or RPE cells, the only accepted route by ophthalmologists Future of drug and therapeutic development: Transcorneal electrical stimulation (TES) for the treatment of retinal and neuronal degenerative disease. Hybrid engineering and pharmacologic strategies Stem cell therapeutics alone and in combination with TES. Variation in Drug Responsiveness: Idiosyncratic drug response: An unusual response that’s not frequently observed in the majority of patients. Quantitative variations in drug response: ○ Hyperreactive: the intensity of effect for a giver dose of a drug may be increased. ○ Hyporeactive: diminished effect in comparison with that observed in most individuals The intensity of response to a drug dose may change during the course of therapy. Response may be decreased (desensitization) or increased (supersensitivity) Reduced responsiveness upon drug exposure: ○ Tachyphylaxis: describes the rapid development of diminished responsiveness after administration of a drug. ○ Pharmacodynamic tolerance: A decreased responsiveness to pharmacologic or hormonal stimulation that occurs slowly over time. Clinical Selectivity: Beneficial vs Toxic Effects: No drug causes only a single specific effect. Accordingly, drugs are selective rather than specific in their actions ○ A drug may act at only one type of receptor but in many different cell types/tissues that express the receptor. ○ Drugs may also act at more than one class of receptor. Routes of administration corresponding to time to effect: Intravenous: 30-60 minutes Endotracheal: 2-3 minutes Inhalation: 2-3 minutes Sublingual: 205 minutes Intramuscular: 10-20 minutes Subcutaneous: 15-30 minutes Receta: 5-30 minutes Oral ingestion: 30-90 minutes Transdermal (topical): Variable (minutes to hours). Week 2: Principles of Pharmacokinetics Effects of a Drug: Desired effects are therapeutic ones, undesired effects are side effects, adverse effects, and toxic effects. Therapeutic effect: The expected ore predictable physiological response a medication cases Side effect: unintended secondary effects a medication predictably will cause when administered at the normal dose. ○ Usually mind, such as nausea, constipation or sensitivity to light ○ Patient can continue to take the medication and manage its side effects Adverse effect/reaction: sever side effect that can cause severe harm or death such as hallucinations, hypotension, or anaphylactic shock Toxic effect: may develop after prolonged intake or accumulation of drug in the blood due to impaired metabolism or excretion or excessive amount taken. Time-plasma drug concentration curve: Common PK terms: Maximum plasma concentration = Cmax Time when Xmas is achieved = Tmax Area under the concentration-time curve = AUC ○ Drug exposure PK usually correlates with clinical endpoints (efficacy/toxicity/biomarkers). T1/2 = Half life of drug ○ Time taken for the concentration to decrease by 50% ○ Useful for determining time the patient is exposed to drug Oral Bioavailability: Bioavailability is a term used to describe the percentage (or the fraction F) of an administered dose of a xenobiotic that reaches the systemic circulation. How much the drug becomes completely available to its intended biological destinations. The level or traction of drugs available in the blood after administration: measured by Tmax or AUC. Bioavailability (F): AUCOral/AUCIV. Bioavailability can be depended on the rate of absorption where factors such as: ○ Rate of drug dissolution (which in turn is depended on chemical structure ○ Product pH partition coefficient surface area of absorbing region ○ First pass metabolism as a determining factor. Steady State: After multiple dosing, at a certain time, rate of drug input = rate of elimination, causing almost constant drug concentrations Maintaining a therapeutic concentration: ○ TDM optimizes a patient’s drug therapy through determining plasma concentrations (therapeutic drug monitoring). ○ TDM is essential for drugs with narrow therapeutic windows such as phenytoin, digoxin, lidocaine, and theophylline. Absorption: Process by which unchanged drug proceeds from site of administration to systemic circulation where measurements are made. Drugs are absorbed/transported via the following mechanisms: ○ Passive diffusion ○ Facilitated diffusion (carrier-mediated, no energy input) ○ Active transport (carrier mediated, with energy input) Drug Concentrations: IC50: concentration of an inhibitor where the response is reduced by half IC95 the concentration needed to inhibit replication by 95% in vitro EC50 concentration of a drug that gives half-maximal response ED95: the effective dosage needed to inhibit replication by 50% in vivo Parameters affecting absorption: Drug’s physical chemical parameters ○ Molecular weight-solubility ○ Formation and ionization Physiological factors affecting drug absorption ○ Gastric pH and buffering system Factors involving oral absorption: Disintegration of dosage form, dissolution of particles, chemical stability of drug, stability of drug to enzymes, motility and mixing in GI tract, presence and type of food, passage across GI tract wall (charge, size, lipophilicity), blood flow to GI tract, gastric emptying time, drug formulation. Drug Distribution: Various transport processes which deliver it to body areas (liver, kidney, skeletal muscle, bone, brain, etc) These transport processes are referred to as drug distribution and are evidenced by the changing concentrations of drugs in various body tissues and fluids. Determined by: partitioning across various membranes, binding to tissue components, binding to blood components (RBC, plasma protein), physiological volumes. Mathematically expressed by Vd = Amount of drug in body/Plasma concentration Clinical Implications of changes in protein binding: Many drugs bind to plasma proteins ○ Albumin (acidic drugs, e.g warfarin, NSAIDs). ○ alpha-I acid glycoprotein (basic drugs, e.g quinine) ○ Lipoproteins (basic drugs) ○ Globulins (hormones) Only free drug can bind to receptor Changes in protein binding capacity: disease and nutrition, protein binding displacement interactions (e.g valproate displances phenytoin, increasing free phenytoin) Clinically relevant effects if: ○ 90% of drug is protein bound, e.g phenytoin, warfarin ○ Small volume of distribution. Protein binding: HSA and other plasma proteins bind drugs Only unbound fraction can interact with enzymes or receptors Only unbound fraction is excreted by kidney Compounds can compete for binding sites on HSA and tightly bound compounds can have suddenly high free fractions when displaced by other compounds. Albumin: binds many acidic drugs and few basic drugs B-globulin and an I-acid glycoprotein have also been found to bind to certain basic drugs. Drug Elimination: The processes drug (xenobiotics) removal from the body Two major processes and responsible organs ○ Metabolism: The liver ○ Excretion: The kidney (major), the bile, etc. Mathematically, drug elimination is expressed by drug clearance (CL) Elimination → excretion and drug metabolism (biotransformation). Drug Metabolism: The chemical modification of drugs Enzymatic or chemical transformation of drugs or endogenous compounds into compounds that are easier (more hydrophilic/polar/water soluble) to eliminate from the body. Enzymes are typically involved in metabolism aka biotransformation Order of pharmacokinetic Profiles: The order expresses the relationship between the elimination rate (K) and the drug concentration In zero order, k is not dependent on the drug concentration, the quantity of drug eliminated per unit time is fixed. ○ There’s no fixed half life. In the first order, k is dependent on the drug concentration. The quantity of drug elminited per unit time is varied. Half-Life t1/2: The time it takes for half of drug to be eliminated from the body t1/2 = 0.693/k To calculate the amount of drug left after y half-lives when A mg of the drug has been dosed: A X (½)y Oral Bioavailability: Bioavailability: rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action ○ Compare between IB and oral administrations as some oral meds aren’t highly bioavailable. ○ Knowing this helps us converts for patients who need other administration routes It measures the extent to which the dose reaches systemic circulation. Factors affecting bioavailability of orally administered drugs: 1. Formulation of drug product: factors include tablet disintegration time or dissolution time. 2. Interactions with other substances in GI tract: complex formation, co-precipitation (e.g mineral oil taken as a laxative can dissolve highly lipid-soluble drugs, impairing their absorption. 3. Biotransformation before a drug gets into systemic circulation: breakdown by intestinal enzymes, intestinal bacterial enzymes, intestinal wall cell metabolism, hepatocyte metabolism. Phases of drug metabolism: Phase 1: Activation/Detoxification: ○ Biotransformation reactions: oxidation, reduction and hydrolysis ○ Polar groups introduced, more water soluble, less lipophilic Phase 2: Detoxification ○ Conjugation reactions ○ Reactions most often abolish biological activity ad add more polarity ○ Very water soluble Inhibitors and inducers: Inhibitors: inhibits the activity of CYP450 enzymes ○ Cimetidine prolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs) Inducers: increase the activity of CYP 450 enzyme ○ Barbiturates, carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents. Variability in expression/activity of drug metabolizing enzymes: Smoking - induces CYPIA2 Alcohol - induces CYP2EI Charbroiled meats: induced CYPIA2 Environmental Factors: Tobacco smoke, smokers metabolize drugs more rapidly than non smokers; Pollutants are capable of inducing P450 enzymes, such as hydrocarbons present in tobacco smoke, charcoal broiled meat induce CYP IA. Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than those who are non exposed. Polychlorinated biphenyls used in industry, cruciferous vegetables also induce CYP IA. Food-Drug Interaction: May decrease absorption: calcium containing foods, tetracycline, high fiber foods Drug-food interactions may increase absorption: high calorie food more than doubles the absorption of saquinavir Drugs may cause an upset stomach if taken without food. Grapefruit juice may inhibit metabolism of certain drugs, raise the blood levels (co-administration of grapefruit juice produces a 40% increase in blood levels of felodipine drug for hypertension), and lead to toxicity levels. Grapefruit juice may inhibit cytochrome CYP3A isoenzymes and decrease metabolism of certain drugs: One glass (200 ml) is sufficient. Excretion: The main process is that the body eliminates “unwanted” substances. Lipophilic drugs may require several metabolism steps before they are excreted Excretion of drug can occur through: ○ Bile (Can potentially be reabsorbed) ○ Urine Filtration of water soluble, small molecular weight compounds into urine in kidneys Active secretion Reabsorption ○ Other routes: Lungs (though exhalation), skin (though perspiration), etc. Drug Clearance (CL): One of the most important ADME parameters for discovery scientists Represents how rapidly a compound is extracted from the systemic circulation (liver and kidney mediated) ○ Urinary excretion ← Kidney ⇔ Liver → Metabolism → biliary excretion Processes in which the body removes foreign bodies (drugs) from the body. It’s a quantitative measure characterizing the rate of removal of endogenous or exogenous substances, including drugs, from the body or a specific portion of the body. Clearance is expressed as the volume of body fluid from which a drug is removed per unit time. Ceriatric Pharmacological Consideration: Increased body fat (25-30%) reduced plasma levels of lipid soluble drugs Decreased total body water by 25% increases concentration of water soluble drugs and intensity of response, greater risk for dehydration Concentration of serum albumin, malnourishment decreased albumin and results in increased drug levels Decreased metabolism: hepatic functions in elderly and drug levels increase. Multiple Factors Affecting Dosing: Genetic Polymorphisms: ○ Pharmacokinetic: ADME, what the body does to the drug ○ Pharmacodynamic: Receptors, Ion channels, enzymes, immune system. What the drug does to the body. Diseases, age, genetic, and ethnic differences can cause changes in pharmacokinetics of drugs that may affect the outcome of drug therapy. The influence of many diseases on pharmacokinetics of drugs is not adequately studied. The study of pharmacokinetic differences of drugs in various population groups is referred to as Population Pharmacokinetics. Week 3: Principles of Drug Action and Pharmacodynamics Pharmacodynamics: Study or science of the effects of medications on the human body Actions and effects of drugs in relation to their chemical structure, what a particular drug does to the body, biochemically, physiologically and how does it do it? Mechanism of action: how a drug achieves its effect at the site of action For a response to occur communication/interaction must occur (signaling) ○ Recognize the drug ○ Respond in an efficient manner ○ Have enough receptors responding to make a difference ○ Have the drug be potent enough to make the response happen Morphine (example): Therapeutic effect: reduce moderate to severe pain Side effect: drowsiness, nausea, constipation Adverse effect/reaction: rash dependence, addiction Toxic effect: respiratory depression → death For drugs to cause a response—simplified: Drug is administered to the patient, absorbed and distributed to where they need to “work” ○ Antipsychotic medications work mostly in the brain When the drug gets to its desired organ.body system the drug acts as the signal ○ “Brain needs less dopamine” How do cells receive the signal? ○ The drug needs an audience/something to receive the message ○ Neurons have receptors that the antipsychotic can dock on and start signaling. Cellular Signaling: Cells require a method to communicate information about their intracellular and extracellular environments Signal transduction allows a cell to receive and transduce information from its intra and extracellular environments and when appropriate, to produce an appropriate cellular response to the signals. The components (cellular machinery) of signal transduction pathways are diverse and include proteins, lipids, small molecules and ions. Signal transduction pathways are analogous to the nervous system of a cell. Every signal that affects a cell does so by influencing at least one effector molecule that in turn generates a response. Sensing of the extracellular environment: In the majority of cases, specialized transmembrane proteins called receptors are the key molecules that transmit signals from the exterior to the interior of the cell Signal transduction allows a cell to receive information from its external environment and to coordinate a response to the signal. Cell signaling occurs daily: norepinephrine/noradrenaline: both a hormone and a neurotransmitter Part of the catecholamines family: epinephrine, norepinephrine, domaine NE plays a role in: ○ Sleep-wake cycle, helping you wake up, increasing attention and focusing on performing a task, memory storage. Low NE: depression, post-traumatic stress disorder, low blood pressure, low HR Overactivation of NE: increase in HR, blood pressure, anxiety Cell signaling can be divided into three stages: 1. Reception: detection of signaling molecule from the outside of the cell a. A signal is detected when the chemical signal (aka ligand) binds ot ta receptor protein b. Can be outside or inside the cell 2. Transduction: receptor confirmation change → initiates the process of transduction a. Signal transduction is usually a pathway of several steps b. Each replay molecule in the transduction pathway changes the next molecule in the pathway (adding or taking away phosphate groups) c. Signal amplification: increasing a signal so that minimal receptor occupation by small amounts of neurotransmitters in the synapse produces significant cellular responses 3. Response: signal triggers a specific cellular response a. Termination happens after the cell elicits a response Receptor mediated drug action: Recognition sites: ○ Recognize with great selectivity specificity ○ Bind with high affinity (EC50 = μM to nM) Effector: ○ Signal regeneration ○ Transduction of binding signal ○ Mechanism based on conformational change of the receptor – >change in function Amplification: ○ Ion transport, enzyme activation/deactivation, protein synthesis. Types of signal transducing messengers; First messengers: ligands can be agonists/antagonists ○ I.e Hormones, neurotransmitters, pharmacological agonists ○ Your drug works as the first messenger Second messengers: molecules that transmit signals received at receptors ○ cAMP, cGMP, DNA binding, ions Drug Binding and Types of Responses: Medications alter the body’s control systems by binding to a constituent of a cell or organ to alter its function and affect the physiological system to which it’s attached Drug receptor: any portion of a tissue or cell to which a drug can bind and initiate its effects ○ Receptors are proteins that are inside or on the surface of a cell that mediate the drug activity ○ A chemical/drug (ligand) binds to a specific site (receptor) to trigger a response Physiological receptors: Many drug receptors are proteins that normally serve as receptors for endogenous regulatory ligands. ○ Drugs commonly alter the rate or magnitude of an intrinsic cellular or physiological response rather than create new responses ○ Agonists: Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds ○ Antagonists: Drugs that block or reduce the action of the natural agonist Not all drug targets are receptors ○ Aluminum and magnesium hydroxides [Al(OH)3 & Mg(OH)2] reduce gastric acid chemically, neutralizing H+ with OH- and raising gastric pH. ○ A large percentage of the new drugs approved in recent years are therapeutic biologics, including genetically engineered enzymes and monoclonal antibodies. ○ Gene therapy products using viruses as vectors to replace genetic mutations that give rise to lethal and debilitating diseases have already been approved in China and Europe. Receptor Types - One drug targets: G Protein-coupled receptors Enzyme linked receptors Intracellular Ligand-gated ion channels G-Protein Coupled Receptors: Chemical signal bind as a ligand to a G protein-linked together G protein linked receptors change shape and interactions with a G protein. Interaction causes GDP to be displaced and GTP to be bound to the G protein The active G protein binds to another protein, usually and enzyme The enzyme is activated and G protein hydrolysis GTP back to GDP G protein releases from the enzyme and the reaction stops. GPCRs: are important regulators of nerve activity in the CNS and are receptors for the neurotransmitter of the peripheral autonomic nervous system. Has 7 transmembrane domains linked to G-proteins G proteins can activate enzymes Human GPCRs are targeted in about 30%R of marketed drugs Enzyme linked receptor: Ligand regulated transmembrane enzymes Polypeptides that cross the plasma membrane Consists of extracellular hormone binding domain and a cytoplasmic enzyme The enzymatic domain may be tyrosine or a serine kinase or guanylyl cyclase Intracellular receptors: Not membrane bound, are found in cytosol that bind onto biological compounds (e.g steroid hormones like glucocorticoid, testosterone and estrogen) Receptors bind to promoters to stimulate the transcription of genes in the nucleus, they are termed “GENE ACTIVE” Therapeutic consequences of gene active receptors: ○ There is a lag period of 30 minutes to a few hours, the time required for new protein synthesis The effects of these agents can persist for hours or days after the agonist is no longer present Examples: Estrogen binding, estrogen receptor dimerization, translocation to nucleus Estrogen response elements (ERE) binding Slow transcriptional response Ion Channels as Receptors: These receptors transmit their signals by increasing the flow of relevant ions and altering the electrical potential across the membrane Examples of transmitters include acetylcholine, GABA and the excitatory amino acids (e.g Glutamate, aspartate). Time between the binding and response can be measured in milliseconds. The rapidity of this signaling mechanism provides rapid information transfer across the synapse. ○ Example: Nicotine stimulates the release of catecholamines, activating nicotine acetylcholine receptors. Features of receptors: Protein: lipoprotein, glycoprotein with one or more subunits Different tissue distributions Drug binding is usually reversible and stereoselective Specificity of binding is not absolute, leading to nonspecific effects. Receptors are saturable because of their finite number Agonist activation results in signal transduction Signal can be amplified by intracellular mechanisms Drugs can enhance, diminish, or black signal generation or transmission Can be up-regulated or down-regulated. Drug binding to Receptors: Types of chemical bonds and attractive forces between the molecules that are pertinent to the interaction of drugs and their active sites. Decreasing bond strength: Covalent (strongest), ionic, hydrogen, hydrophobic, van der waals (weakest). Dose and Concentration: Dose: quantity of a medicine or drug taken or recommended to be taken at at particular time Concentration: amount of a drug in a given volume of blood plasma, measured as the number of micrograms per milliliter EC: effective concentration ○ EC50: The drug concentration producing 50%V of maximan effect ED: effective dose ○ ED50: The drug dose producing 50% of maximal effect TD: toxic dose ○ TD50: The dose producing a toxic effect in 50% of the population LD: lethal dose ○ LD50: the dose producing a lethal effect in 5% of the population ○ LD values almost always refer to animal studies, since lethal doses in humans are rarely known within any accuracy. Specificity, Potency, Efficacy: Specificity: when a drug is able to bind with a specific cell site, either on its cell membrane or within the cell Potency: amount of drug required for given response ○ More potent drugs produce biological effects at lower doses or concentrations, and have a lower ED50 Efficacy: extent to which a drug can produce a response when all available receptors or binding sites are occupied (Emax on dose response curve). Specificity of Drug Action: No drug is entirely specific in the sense that it acts exclusively only on one type of cell or tissue, having just the desired effect and no other. Drugs vary in their specificities and the usefulness of a drug clinically is often directly related to its specificity Poisons have deleterious effects on cell function without having any therapeutic effects. Eg., cyanide combines strongly with the Fe3+ found in many proteins interfering in their functioning. Some drugs have absolutely no toxicity at concentrations used clinically. ○ Eg., penicillin inhibits a bacterial enzyme involved in the formation of bacterial cell walls. Humans, lacking cell walls, are unaffected by these concentrations of penicillin. In between these two extremes (cyanide & penicillin) are many drugs that are used clinically Generally, useful therapeutic effects of drugs may be separable from the toxic effects based on their differences in: ○ Their respective mechanisms of action ○ Their dose-response relationships if their mechanisms of action are similar ○ The sites at which therapeutic and toxic effects are produced Molecular selectivity of drugs binding to specific receptors helps in the development of new therapeutic agents displaying fewer side effects. Raclopride is a highly selective antagonist of dopamine D2 and D3 (but not D1, D4 or D5) receptors. It is a potent antipsychotic agent used in the treatment of schizophrenia. ○ Use of raclopride leads to fewer of the troublesome side effects (eg., antipsychotic-induced Parkinsonism) that are seen when all dopamine receptor subtypes are blocked. The use of specific antagonists also helps in understanding disease mechanisms. That D1 receptor specific antagonists have no utility in the treatment of schizophrenia tells us that dopamine actions at D1 receptors are not important in schizophrenia. Agonism: Agonists: binds to receptors → activate receptors → results in a biologic response ○ Levopheled (norepinephrine) mimics norepinephrine in the body to raise blood pressure Full agonists results in maximal response by occupying all or a fraction of receptors ○ Full agonist will have the greatest efficacy and can produce the maximum response of which the receptor is capable ○ Larger stimulus to cellular signaling machinery → large effect Partial agonist results in less than a maximal response even when the drug occupies all of the receptors: ○ Lower efficacy, even when all receptor sites are occupied. ○ Small stimulus to cellular signaling machinery → small effect Antagonism: Antagonists: bind to receptor → nop biological response Reversible competitive antagonist: inhibition that can be overcome by increasing the concentration of the agonist ○ Rightward shift of the log concentration effect curve without altering Emax or EC50. Irreversible competitive antagonist: competition between agonist and antagonist for the same receptors but stronger binding forces prevent the effect of the antagonist being fully reversed, even at high agonist concentrations ○ Rightward shift of the log concentration effect curve of the agonist that generally displays decreased slope and reduced maxim effect Noncompetitive antagonist: inhibits agonist activity by blocking the function of the receptor at a different site. Pharmacodynamic Changes: Alterations in receptor levels may change: For example, beta-blockers are less effective in the elderly patients. Age-related changes resulting in sensitivity to certain classes of drugs place the elderly at risk for adverse drug reactions CNS depressants (e.g., benzodiazepines) resulting in delirium, confusion, agitation and sedation Anticoagulants and hemorrhage e.g., in combination with NSAIDs, salicylates. Alpha-blockers resulting in orthostatic hypotension Anticholinergic medications resulting in dry mouth, constipation, urinary retention, blurred vision, confusion Week 3: Introduction to Pharmacogenomics Clinical Applications Gene: Basic unit of heredity, sequence of nucleotide bases Gene → codes for protein DNA → mRNA → Protein Gene encodes all of the information Genome: all the genes in your body Genotype and phenotype: Genotype: two copies of a genetic variant ○ Alleles: two alleles make a genotype ○ Any one of a number of alternative forms of the same gene that occupies a given position on the chromosome Phenotype: observable characteristics that result from a genotype Genetic Polymorphism: Genetic polymorphism refers to a DNA sequencing variation that has a frequency of at least 1%. ○ Single-Nucleotide Polymorphisms (SNPs) are a common example of genetic polymorphism, characterized by single base pair substitutions, insertions, or deletions. ○ SNPs are the most extensively studied and prevalent form of genetic variation. ○ Genetic polymorphisms are defined by a population frequency greater than 1%. Other types of genetic polymorphisms include gene deletions and copy number variants (CNVs). ○ Gene deletions involve the absence or removal of specific genes in the genome. ○ Copy number variants (CNVs) refer to variations in the number of copies of a particular DNA segment in the genome. Pharmacogenetics vs Pharmacogenomics: There’s no universally accepted definitions of either and are often used interchangeably Pharmacogenetics: science about how heritability affects the response to drugs ○ Used for more than 40 years ○ Commonly used to depict the study of single genes and their effects on interindividual differences in (mainly) drug metabolizing enzymes Pharmacogenomics is new science about how the systematic identification of all the human genes, their products, interindividual variation, intraindividual variation in expression and function over time affects drug response/metabolism etc ○ Coined in connection with the human genome project ○ Depict the study of not just single genes but the functions and interactions of all genes in the genome in the overall variability of drugs response Importance of Pharmacogenomics: Drug response varies from one individual to another Individuals experience different side effects Metabolism and elimination varies from person to person Certain diseases are not adequately treated or controlled Goals: ○ Maximize drug efficacy ○ Minimize drug toxicity ○ Predict patients who will respond to intervention ○ Aid in new drug development Benefits of this approach: Because drugs can be dangerous and many people have severe adverse reactions to drugs ○ Many people respond to drugs at different doses ○ Many drug treatments are horribly unpleasant, painful Drugs are expensive (to take and to make) ○ Ineffective drugs are a waste of money to take ○ Drug development needs to account for response variability Genetics provide a priori information ○ Genetics don’t change (except in cancer) ○ Genetics can point to the cause not just the symptom CPIC: CPIC guidelines are designed to help clinicians understand how available genetic test results should be used to optimize drug therapy, not whether tests should be ordered. Key Assumption: ○ Clinical high-throughput and pre-emptive genotyping will become more widespread. ○ Clinicians will be faced with having patients’ genotypes available even if they did not order tests with drugs in mind. Pharmacogenetics Involves Both PK and PD: Pharmacokinetics: The process by which a drug is absorbed, distributed, metabolized, and excreted by the body Pharmacodynamics: The biochemical and physiological effects of drugs and the mechanisms of their actions Variation in drug response is not always genetics: It can be due to age, comorbidities, renal and hepatic function/dysfunction, concomitant medications, diet and smoking Pharmacogenomics Interplay with Drug: Basic principles of pharmacology focus on ideas that drugs will have an activity when they get into the bloodstream. In reality, drugs will work if they have the ability to work with their receptors/target site 2 types of drugs: Active vs Pro Drugs Metabolism plays a key role Active Drugs vs Pro-drugs: Active drugs: ○ Have pharmacologic effect without activation ○ Do not require activation step ○ Active drug with inactive metabolite Pro-drugs: ○ Require activation step for drug to have effect ○ Activation stype is typically done by a metabolizing enzyme ○ Activation creates an active metabolite which has pharmacologic effect. ○ Pro-drug with active metabolite Cytochrome P450: An enzyme family responsible for drug metabolism: CYP450 ○ Family number: CYP1, CYP2, etc… ○ Subfamily number: CYP1A, CYP2D ○ Individual Enzyme: CYP1A2, CYP2D6 (responsible for metabolism) Drugs / Medications are metabolized by different CYP enzymes For ACTIVE drugs, metabolism breaks down active drugs into inactive metabolites For PRODRUGS, metabolism converts that inactive drug into an ACTIVE metabolite How Genes Affect Metabolism: Individuals can have variation in their CYP functioning ○ The CYP genotype (pair of alleles) results in the CYP phenotype (level of functioning) ○ Genotypes vary for each CYP isoenzyme The “wild type” genotype is considered “functional” (the majority of individuals) ○ You get one allele from each parent ○ *1 is considered the “wild type” allele = considered functional ○ *1 / *1 = genotype that would produce a “normal” metabolizer phenotype Phenotypes and Genotypes: Phenotypes (level of functioning) vs genotype (alleles present) Poor metabolizer (PM): two inactive alleles ○ Too slow or no drug metabolism ○ Too high drug levels at ordinary dosage ○ High risk for side effects Intermediate Metabolizer (IM): 2 decreased activity alleles, or 1 active and 1 inactive, or 1 decreased activity and 1 inactive ○ May experience some or a lesser degree of the consequences of poor metabolizers Normal/extensive Metabolizer (NM/EM): 2 functional alleles (wild type) ○ Expected response to standard dose Ultra-rapid Metabolizer (UM): Multiple copies of functional alleles without inactive or decreased function in any ○ Too rapid drug metabolism ○ No drug response at ordinary dosages (non-responders) Why the metabolism phenotype matters: How well a drug is metabolized affects how much drug gets to the bloodstream to have an effect: ○ If too little active drug gets to the bloodstream, it’s less likely the drug will have its intended effect ○ If too much drug gets to the bloodstream, there’s higher risk of side effects Active Drugs: Extensive Metabolizer/Normal Metabolizer (wild-type): ○ CYP1A2 is considered functional ○ Active drug A → CYP1A 2 → normal amount of inactive drugA, normal amount of active drugA → therapeutic effect + small amount of side effects Some of active drug A will get metabolized to an inactive form and some will go on to have a therapeutic effect and fewer side effects are likely to occur Poor Metabolizer: ○ CYP1A2 is considered non-functional/decreased activity ○ Active drug A → PM CYP1A2 → small amount of inactive drugA, large amount of active drugA → small therapeutic effect + large amount of side effects Little drugs will be metabolized and cleared from the body. A majority of the drug will be retained in the body → will see some therapeutic effects but more side effects are likely to occur. Ultrarapid Metabolizer: ○ CYP1A2 has increased activity ○ Active drug A → UM CYP1A2 → Large amount of inactive drug A, small amount of active drug A → Small amount of therapeutic effect + small amount of side effects Majority of the drug will be metabolized and cleared from the body. Little active drug will remain in the body → less likely for therapeutic benefit and side effects to occur. Pro-Drugs: Extensive Metabolizer/Normal Metabolizer (wild-type): ○ CYP1A2 is considered functional ○ Inactive drug A → CYP1A 2 → normal amount of inactive drugA, normal amount of active drugA → therapeutic effect + small amount of side effects Some of active drug A will be converted to its active metabolite to have therapeutic effect and few side effects are likely to occur. Poor Metabolizer: ○ CYP1A2 is considered non-functional/decreased activity ○ Inactive drug A → PM CYP1A2 → Large amount of inactive drugA, small amount of active drugA → small therapeutic effect + small amount of side effects Little of the drug will be converted to the active form. A majority of the drug remains inactive in the body → little therapeutic effect and little side effects are likely to occur. Ultrarapid Metabolizer: ○ CYP1A2 has increased activity ○ Inactive drug A → UM CYP1A2 → Large amount of active drug A, small amount of inactive drug A → Small amount of therapeutic effect + large amount of side effects Majority of the drug will be converted to the active form → high concentration of active form in the body. Will see some therapeutic benefit but more likely for side effects to occur. Notable Pharmacogene-Drug Pairs: Trastuzumab and HER-2: Trastuzumab (Herceptin) and HER-2 (Human Epidermal Growth Factor Receptor 2) ○ HER-2 is a proto-oncogene that can lead to the development of breast, stomach and esophageal cancer ○ Overexpression of this oncogene can lead to rapid cell growth and proliferation ○ HER-2+ cancers tend to be more aggressive, associated with poor prognosis and metastatic disease Trastuzumab targets HER-2+ cells to stop growing ○ Must have HER-2+ cancer to use ○ Normal (non-cancerous) cells also possess low amounts of HER-2 (breast, GI, kidney, and heart). Carbamazepine and HLA Genes: Carbamazepine (anticonvulsant) and HLA-B and HLA-A genes ○ HLA genes encode proteins that present antigens onto the surface of the immune cell. ○ Enables your immune system to recognize what is self and nonself Positive HLA-B*1502 genotype is highly correlated to risk of carbamazepine Steven Johnson’s Syndrome or Toxic Epidermal Necrolysis ○ SJS and TEN are life threatening skin diseases resulting in rash, skin peeling and sores ○ Highest frequency of HLA-B*1502 is found in East Asian, Oceanian, and South/central Asian populations. Nitrofurantoin and G6PD Deficiency Glucose-6-phosphate dehydrogenase is an enzyme that catalyzes reactions to help counterbalance oxidative damage ○ A deficiency in G6PD can lead to hemolytic anemia ○ Red blood cells hemolyze (burst) and there can be severe jaundice, fatigue or dark urine ○ Hemolytic anemia can be triggered by certain foods, medications and medical conditions Nitrofurantoin is an antibacterial medication, used to treat UTIs ○ Hemolytic anemia can develop in those with G6PD deficiency who take nitrofurantoin, When to undergo pharmacogenetic testing: Need to consider risks vs benefits before deciding to take a pharmacogenetic test ○ Some may benefit more than others If someone is not currently taking a medication with a gene-drug pair, they may not benefit from completing gene testing Pharmacogenetics is just one piece to an individual’s response to medication ○ Do not change or stop taking any medications based on the genetic test report ○ Discuss these results with a health care provider A positive test can be stressful and upsetting Protection of Genetic Information: The Genetic Information Nondiscrimination Act (GINA) ○ Prevents health insurers from using genetic information in coverage and rating determinations ○ Prevents employers that have 15 or more employees from requesting or using your genetic information to make hiring, firing or promotion decisions ○ Does NOT cover certain types of insurance including, but not limited to, life, disability and long-term care insurance Why pharmacogenetics is not widely utilized in the clinic: It required a shift in clinician attitude and beliefs “not one dose fits all” Paucity of studies demonstrating improved clinical benefit from use of pharmacogenomic data Even some of the black block warnings currently on drug labels may be overcalls of importance Genome wide interrogation will likely be important to get the entire picture Week 4: Introduction to Drug Discovery and Development The Pharma Value Chain: The many entities and organizational, operational, and value-adding activities involved in developing and delivering pharmaceutical products to the market. Stakeholders include: pharmaceutical manufacturers tha research, develop, and produce drugs. Before target discovery, a library of gene/protein/metabolites (genome, proteome, metabolome) sequences to explore for information. E.g APOE4 gene increased cases of Alzheimer’s Identifying a Drug Target: Drug target - specific macromolecule, or biological system, which the drug will interact with. E.g. FPR2 receptor. Sometimes this can happen through incidental observation Target sites: What is the source of the issue? How can I reach it? E.g target in the liver, oral meds, 1st pass metabolism. Liver (hepatocyte): mTORC1 (controls protein synthesis) → Triglyceride lipid accumulation → NAFLD Heart (cardiomyocyte): mTORC1 → Hypercholesterolemia impaired autophagy → Cardiac Disease Arterial wall (macrophage): mTORC1 → Lipid burden chronic inflammation → Atherosclerosis Side effect is due to hitting other targets. Selectivity: Similar targets may be present (homologous & closely aligned) specificity that it can hit the target. If other targets/receptors are reached, there will be more side effects. E.g targeting a bacterial enzyme, which isn’t present in mammals or which has significant structural differences from the corresponding enzyme in mammals Target Discovery: Comparing control vs disease, is the differential proteins or mRNA or metabolites expressed/not expressed. ○ Genes and gene modification associated with a disease ○ Proteins or protein modifications associated with a disease ○ Regulatory pathways required for disease processes Look for gene/proteins/metabolites essential for infectious agents and distinct from the host. Target validation: Molecular level: ○ Screen enzyme inhibitors or activators Cellular level: ○ Verify the involvement of the protein in the disease state (often use gene silencing siRNAs) ○ Understanding the protein pathways and interactions Organism level: ○ Verify critical nature of target and uniqueness Lead discovery: Discover leads that affect the target gene, protein or pathway: ○ Inhibit/activate a defective protein ○ inhibit/activate expression of a protein/pathway ○ Stimulate protein modifications or cellular location Evaluate leads to ‘cure’ of the problem: ○ Replace missing or defective protein with gene therapy ○ Antisense or siRNA to prevent protein expression ○ Antibody to remove or inhibit protein target ○ Simulation of synthesis to replace or activate proteins ○ Simulate protein modification or location Drug discovery methods: Screening natural products Screening synthetic banks Enhance a side effect use structural similarity to a natural ligand Computer assisted drug design Serendipity Screening natural compound: Plans, microbes, the marine world, and animals all provide a rich source of structurally complex natural products. E.g aspirin, Atropine, caffeine, codeine, morphine Screening synthetic banks: Pharmaceutical companies have prepared thousands of companies These are stored in the freezer and cataloged and screened on new targets as these new targets are identified. “Which of the following can inhibit/enhance this target?” Computer assisted drug design: If one knows the precise molecular structure of the target molecular structure of the target, then one can use a computer to design a perfectly fitting ligand. Drawbacks: ○ Most programs don't allow conformational movement in the target (as ligand is being designed and or docked into the active site ○ Cannot evaluate intrinsic activities ○ Thus most programs are somewhat inaccurate Enhance a side effect: Sulphanilamide: antibacterial with side effect of lowering glucose levels in blood also diuretic activity Tolbutamide: compound which has been optimized to only lower blood glucose levels. Useful in treatment of type II diabetes Chlorothiazide: a compound which has been optimized to only display diuretic activity Structural similarity to natural ligand: 5-hydroxytryptamine (5-HT): serotonin (a natural neurotransmitter synthesized in certain neurons in the CNS) ○ Natural drugs in our body are endogenous molecules Sumatriptan (Imitrex): Used to treat migraine headaches, known to be a 5-H1 agonist, similar structure to serotonin Serendipity: A chance occurrence: Accidental discovery by an experimentalist: ○ Understands the big picture and is not solely focused on his/her immediate research goal ○ Open mind toward unexpected results ○ Use deductive logic in the explanation of such results ○ E.g penicillin and viagra for ED. Lead Identification: At this state, validated hits would be tested to determine factors such as: ○ Selectivity vs a panel of other receptors (target) ○ Physicochemical characteristics (e.g hydrophilic/lipophilic. Lipophilic will have a higher volume of distribution, can it pass through the BBB?) Indication of administration ○ Drug-like properties ○ Metabolic properties (half-life, etc) ○ Those molecules with acceptable potency, physical, and ADME properties can be advanced through lead optimisation. ○ Dose likely to be unknown at this point Those molecules fulfilling the lead identification criteria can go to molecular finishing school ○ At this stage, medicinal chemistry conduct extensive SARs to improve potency and selectivity ○ Also, this is the opportunity to improve physicochemical and drug like properties Involves molecular bioscientist, medicinal chemist, pharmacokinetics group, formulation group, clinical researchers, marketers among others. Structure-activity-relationship (SAR): Once a lead has been discovered, it is important to understand precisely which structural features are responsible for its biological activity (i.e. to identify the “pharmacophore”) The pharmacophore is the precise section of the molecule that is responsible for biological activity, which cannot be touched Lead discovery: Modification may be done through synthetic modifications ○ Yield more active molecules ○ Eliminate “excessive” functionality ○ Reduce toxicity and cost of production of the active material Example: ○ R-OH can be converted through R-OCH3 to see if O-H is involved in an important interaction ○ R-NH2 can be converted to R-NH-COR’ to see if interaction with positive charge on protonated amine is an important interaction Applications: ○ When the field has been narrowed down after being tested against the target. the best molecules are advanced to animal models and preliminary toxicology. Selecting the best candidate: ○ The smaller your EC50, the more potential the drug has ADMET: Ideal properties of drugs: Absorption: passes GI tract into the bloodstream Distribution: gets to target tissue (BBB) Metabolism: Not readily metabolized Excretion: Not readily excreted Toxicity: Not toxic to other cells or tissues Lipinski’s rule of five: Doesn’t apply to neuro drugs Fewer than 5H bond donors (which can be estimated by counting the total number of OH and NH groups in the molecule Fewer than 5H bond acceptors (estimated by the total of N and O atoms in the molecule) A molecular weight of less than 500 A partitioning coefficient (logP) of less than 5 ○ Partition coefficient measures how hydrophilic or hydrophobic a chemical substance is ○ The greater the solubility of a substance, the higher its partition coefficient, and the higher the partition coefficient, the higher the permeability of the membrane to that particular substance. Candidate Selection: At this stage, those optimized leads are scrutinized for their properties: ○ Potency ○ Selectivity ○ Bioavailability ○ Intellectual property (IP) position ○ Safety ○ Scale up potential (can you make enough of it cheaply enough?) ○ The data on the successful candidate will then be submitted to the appropriate health authorities to get permission to conduct clinical investigation. Anti Inflammatory drugs act on COX The case of AA Pathway: ○ LXA4 and NAP1051 ○ Lots of similarities, difference is NAP1051 has a longer half-life and anti-inflammatory A drug on the market was modified Implications: uses for arthritis, and antiinflammatory ○ Should we expect differences in PK/PD? Less soluble in water so it can’t be put in solution. Within oil an injected intravascular or topical Good drug but consider the device to deliver it. Strategies for dealing with drug solubility: Common strategies to address low drug solubility: ○ Co-solvents ○ Salts: e.g ziprasidone HCL and diclofenac sodium ○ Surfants ○ Cyclodextrins ○ Particle size reduction ○ Lipid-based systems ○ Co-crystals ○ Amorphous solid dispersions Cyclodextrin and drug solubility ○ Cyclists are very soluble in water, but the inner part of the bucket is very lipophilic, outside hydrophilic ○ Bucket structure allows lipid drug to be included in hydrophobic cavity while outside improves solubility in water. ○ Formation of inclusion complexes with cyclodextrins or calixarenes can enhance drug solubility through several mechanisms: Increased surface area: The inclusion complex increases the SA available for drug dissolution, allowing more efficient interaction with the surrounding solvent. Disruption of drug aggregation: Poorly soluble drugs often tend to aggregate, reducing their solubility. Inclusion complexes disrupt drug aggregation and keep the drug molecules dispersed, enhancing solubility. Facilitated transport: Inclusion complexes can enhance the transport of drug molecules across biological membranes, such as the intestinal epithelium, leading to improved absorption and bioavailability. Choosing the bioassay: Drug testing may be conducted in these systems: ○ In vitro: in an artificial environment, such as in a test tube or culture media ○ In vivo: in the living body. Referring to tests conducting in living animals ○ Ex vivo: refers to doing the test on a tissue taken from living organism In Vitro Testing Benefit: speed, requires relatively small amounts of compound Speed may be increased to the point where it is possible to analyze several hundred compounds in a single day (high throughput screening) Results may not translate to living animals In Vivo Testing: More expensive May cause suffering to animals Results may be clouded by interference with other biological systems Determine toxicity and efficacy in animal models Mouse vs pig vs dog: can control genetics of a mouse, ability to control the system/environment. Mice are smaller and easier to manage. Indication, which animals have similarities with humans? Rabbit → eye. Disease model. Preclinical Testing: These questions should be answered: ○ Is the drug safe ○ Affects other body systems? ○ Effective dose range? ○ Pharmacodynamics? ○ Pharmacokinetics ○ Is the drug a carcinogen? ○ Is the drug a teratogen? ○ Long term animal studies confirm cancer or birth defects Investigational New Drug: Investigational new drug (IND): application for permission to administer a new drug to humans Outlines the proposal to use the new drug for human testing in clinical trials Studies in humans can only begin after IND is reviewed and approved by the FDA and Institutional Review Board (IRB) Good Laboratory Practices: GLP are laws that are intended to support appropriate practice in research and development They pertain to processes and conditions under which clinical and nonclinical research of pharmaceuticals, devices, and biologics for humans and animals should be planned and connected. Handle testing facility and enforces the principles They discuss how the studies should be monitored and reported, and how the record from these studies should be stored. They discuss how facilities in which clinical and nonclinical studies are conducted should be maintained However, they do not pertain to the manufacturer of products Good manufacturing practices: This ensures that pharmaceuticals, divides, and biologics are produced according to: ○ Consistent standard ○ Good quality and ○ Appropriateness for intended use GMP requires pharmaceutical companies to have processes that assure the adequate manufacturing control. Good Clinical practice: Universally recognized international standards/guidelines on the design and conduct of clinical trials Protects the rights, safety, and well-being of trial participants Describes the responsibilities of everyone who conducts clinical trials Covers the conduct and monitoring of clinical trials Describes reporting of data and records retention. Definition of GCP: a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected.” Quality Data + Ethics = GCP Data and Reported Results are Credible, and Accurate = Quality data Rights, Integrity, and Confidentiality of Trial Subjects are Protected = Ethics Clinical Trial: Research studies that test a medical, surgical or behavior intervention in people Involves a team of investigators Who’s involved: Investigators, coordinators/project managers, nurses, clinical officers, fieldworkers, pharmacists, data manager and entry clerks, monitor/QA, laboratory staff and possibly data safety and monitoring board, clinical trial steering committee. Different types of clinical trials: Treatment trials: test new treatment, new combinations of drugs, or new approaches to treat a disease Prevention trials: test for better ways to prevent disease in people who’ve never had the disease or to prevent a disease from returning Screening trials: test the best way to detect certain diseases or health conditions Diagnostic: how can new tests or procedures ID disease Quality of life trials/supportive care: explore ways to improve comfort and quality of life for individuals with a chronic illness Phases of clinical trial: Phase 1: 20-100 healthy volunteers: ○ Is the drug safe? ○ Are there any serious side effects? ○ How does the drug dose relate to any side effects ○ Is the vaccine causing an immune response? Phase 2: Several hundred volunteers ○ What are the most common short term side effects ○ What is the body’s immune response? ○ Are there signs that the vaccine is protective? Phase 3: 1000+ volunteers: ○ How do disease rates compare between people who get the vaccine and those who do not? How well can the vaccine protect people from the disease Phase 4: Vaccine approved ○ FDA approve a vaccine only if it’s safe, effective and benefits outweigh the risks ○ Researchers continue to collect data on the vaccine long-term benefits and side effects Phase I: Is the drug safe and tolerable? Does the PK differ much from animal to man? → linearity Does it show proper absorption, bioavailability? Can we detect effects unrelated to the expected action? Is there any predictable toxicity? Subject considerations: ○ First in a small group of 12 to 25 ○ Inclusion criteria (informed consent is a must) ○ Healthy volunteers, expect for toxic drug, e.g Anti HIV, anti-cancer ○ Exclusion: women of child-bearing age, children Start with a dose about 1/10 - ⅕ tolerated animal dose Slowly increase the dose to find a safe tolerated dose No blinding Centre has emergency care and facility for kinetics study performed in a single center Takes 3-6 months - 70% success rate. Phase 2: First in patient (diff from healthy volunteer) Early phase 20-100 patients with relevant disease ○ Therapeutics benefits and ADRs evaluated establish a dose range to be used in late phase ○ Comparison with standard drug Late phase 50-100 patients ○ Double blind ○ Compared with a placebo or standard drug ○ Outcomes: Assesses efficacy against a defined therapeutic endpoint Detailed PK and PD data Establishes a dose and a dosage form for future trials Takes 6 month to 2 years 35% acceptance rate Phase III: Large scale, randomized, controlled trials About 250 - 20,000 patients Performed by clinicians in the hospital Minimises errors of phase I and II Effectiveness of the new treatment against effectiveness of current treatments Methods: ○ Multicentric → ensures geographic and ethnic variations ○ Different patient subgroups e.g pediatric, geriatric, renal impaired ○ Randomized allocation of test drug/placebo/standard drug ○ Double blinded: Document all adverse drug reactions Rigorous statistical evaluation of all clinical data ○ Takes a long time: up to 5 years: 25% success Phase IV or post marketing surveillance: No fixed duration/patient population Starts immediately after marketing Ensure it is yielding the required effects Report all ADRs Helps to detect: ○ Rare ADRs ○ Drug interactions ○ Also new uses [sometimes called phase V] Week 6 - Pharmacotherapy considerations in the Elderly Trends in aging: Decline in premature death in the elderly and their overall better health are likely due to: ○ Public health measures affecting all age groups, such as expanding immunizations and good prenatal care ○ Advances in medical technology ○ Promotion of a healthy lifestyle ○ Improvements in living conditions ○ Improved public health campaigns and screening ○ Behavior changes (smoking cessation) Trends in geriatric care: US expenditures for healthcare are already the highest among developed nations, but are expected to rise further as chronic disease affect growing number of geriatric patients Among healthcare costs for older americans 95% are for chronic diseases The cost of providing healthcare for one person aged 65 or older is 3-5 times higher than the cost for someone younger By 2030 healthcare spending will increase by 25%, as the population ages, this estimate does not take into account inflation and the highest costs of new technologies. Medication related problems: Older adults account for 49.8% if hospital admissions due to adverse drug events – rate is greatest for age 85+ years Adults age 50+ account for 51.1% of ED admissions for adverse drug events Hospital readmissions (hospice) Preventable medication errors: ○ Renal and hepatic function ○ Drug interactions ○ Lack of individualized therapy Age associated Issues: Physiologic changes affect both pharmacokinetics and pharmacodynamics Reduced physiologic reserve narrows the margin for error Polymedicine increases the risk for adverse reactions and drug interactions Multiple providers and self-care both increase the risk for inappropriate medication use. Changes in geriatric patients: Increase in body fat (25-30%) reduces plasma levels of lipid soluble drugs Decrease total body water by 25% increases concentration of water soluble drugs and intensity of response, greater risk for dehydration Decrease concentration of serum albumin: ma;nourishment decrease albumin and results in increased drug levels Decreased metabolism: hepatic functions in elderly and drug levels increase (diazepam, theophylline) Changes in Geriatric Patients: Stomach pH increases, blood flow decreases, decrease in gut motility (slow onset) In the elderly muscle decreases by 25% Excretion: decline (40-50% of renal functions in elderly may lead to higher serum drug levels and longer drug half-life. Reduced renal clearance of active metabolites may enhance therapeutic effect or risk of toxicity (digoxin, lithium, aminoglycosides, vancomycin). Age associated changes: Area Change Function General Decreased height, weight Increased fat Decreased total body water Altered drug distribution Cardiovascular Tortuosity of arteries Arterial thickening Arterial fibrosis Sclerosis of heart valves Decrease CO Decrease HR response Decreased arterial compliance Renal Abnormal glomeruli Decreased RBF, ClCr Decreased max urine osmolality Skin Wrinkling Sweat gland atrophy Altered thermoregulation Lung Decreased elasticity Decreased ciliary activity Decreased vital capacity Decreased maxim O2 uptake Decreased cough reflex GI tract Decreased HCl, saliva flow Fewer taste buds Decreased cholinergic activity Altered absorption Reduced taste sensation Decreased bowel motility Eyes Decreased pupil size Growth of lens Decreased accommodation and acuity Decreased color sensitivity Decreased depth perception Hearing Ossicle degeneration Eustatian tube obstruction Atrophy of external ear and cochlear hair cells Loss of auditory neurons Decreased high frequency hearing Decreased pitch discrimination Nervous system Decreased brain weight Decreased cortical cell count Decreased transmission speed Receptor alterations Immune system Decreased T-cell activity Drug Distribution: Factors leading to altered distribution ○ Decreased: Lean body mass Total body water Serum albumin Cardiac output ○ Increased: Total body fat Alpha1-acid glycoprotein Factors leading to altered metabolism: Reduced liver mass and volume Decreased hepatic blood flow Altered enzyme activity ○ Sex and genetic differences ○ Age associated declines ○ Drug interactions Nutrition and health status Decreased Decreased/Unchanged Unchanged CYP1A2 CYP2C19 CYP2A CYP2C9 CYP3A4 CYP2D6 Other factors: ○ Induction - smoking/alcohol ○ Induction/Inhibition - drugs ○ Variable: Diet ○ Inhibition, if severe: Malnutrition ○ Inhibition: Frailty CNS Changes: Reduced blood flow and oxygenation Increased MAO levels Decreased norepinephrine, dopamine More sensitive to sedating agents Greater sensitivity to anticholinergic agents Increased permeability of the BBB Cardiovascular changes: Decreased response to catecholamines (hormones made from adrenal glands) ○ Primarily affects beta receptors Increased circulating norepinephrine Reduced cardiac output Increased peripheral resistance Less responsive baroreceptors (a type of mechanoreceptors allowing for relaying information derived from blood pressure within the autonomic nervous system) Endocrine Changes: Impaired glucose tolerance Decreased renal response to hypoglycemia (low blood glucose) Decreased production of sex hormones Decreased thyroid hormone production Prescribing guidelines: Beers criteria ○ Originally targeted to long-term care START criteria ○ Frequently underutilized treatments/meds STOPP criteria ○ Potentially inappropriate medications Therapeutic Malfunction: Hepler and Strand have used the term ‘drug related morbidity’ to describe the phenomenon ○ Therapeutic malfunction: the failure of a therapeutic agent to produce the intended therapeutic outcome ○ Encompasses both treatment failure and the production of new medical problems Appropriate initiation of therapy require the recognition and assessment of the patient’s signs and symptoms to generate an appropriate diagnosis and therapeutic plan Adverse drug reactions in geriatrics: Seven times more likely in elderly ○ 16% of hospital admissions and 50% of all medical related deaths Drug accumulation secondary to reduced renal function Polypharmacy: dangerous practice (drug-drug interactions) Greater severity of illness Presence of multiple pathologies Increased individual variation inadequate supervision of long-term therapy Poor patient compliance Assess: Appreciate, effectiveness, safety, adherence Problems with initiation of therapy: Patient doesn’t report s/sx that may have medications to help treat ○ Problem may be asymptomatic ○ Lack an understanding of significance or meaning symptoms ○ Distrust of providers ○ Lack of access to healthcare due to an inability to pay for services or geographic barriers ○ Selection of starting a drug is challenging Clinically appropriate/effective Const and non clinical challenges Problems in monitoring and managing drug therapy: ‘Clinical inertia’: failure of healthcare providers to initiate or intensify therapy when indicated Clinical inertia due to at least three problems: ○ Overstimulation of care provided ○ Use of soft reasons to avoid intensification of therapy ○ Practice organization not being designed for achieving therapeutic goals ○ Several studies have noted that physicians overestimate their care provided for chronic illness ○ Overestimation of the extent to which they screened and monitored Problems with information flow: Poor flow of information throughout the pharmaceutical care system Clinicians need ○ Timely access to objective and subjective data ○ Evaluate the appropriateness of a prescribed drug via diagnosis, weight, and other medications. Patients need proper communications ○ Therapeutic goals, how to appropriately use the medication, how to self-monitor for side effects and therapeutic effectiveness, and how and when to contact various clinicians Prescribing cascades Best practices for pharmacotherapy: Simplify regimen (once or twice daily dosing) Consolidate medications Use of blister packs, pill boxes, calendars, watches, other reminders Reduce costs (e.g., generics, pill splitting) Summary: Age-associated changes in pharmacokinetics and pharmacodynamics present therapeutic challenges Interpatient variability makes it difficult to predict clinical effects with certainty Disease, nutrition, adherence, other drugs complicate the picture Patients benefit from a “risk management” approach Week 6: Psychotropic Pharmacology Central Nervous System Stimulants Neuron antoi: Direct message travels 85 billion neurons Dendrites, where neurons receive most of the information (input) conduct action potential then response via axon terminal. Receive messages, cascade down electric potential down to the axon covered by myelin sheaths. Methamphetamine is a neurotoxin, axon needs myelin insulation for proper conduction Synaptic cleft: Presynaptic neuron: signal is initiated ○ synthesis , packaging, release of NT Postsynaptic neuron: Signal is received Neurotransmitters act as first messengers in signal transduction Reuptake through transporters Termination of monoamines are done though monoamine oxidase (main metabolizers) an inhibitor would prolong the life spain of those below ○ Dopamine, norepinephrine, and serotonin Neurotransmitter is the first messenger Psychotropic medication: Medication that is prescribed for the treatment of symptoms of psychosis or another mental, emotional, or behavior disorder Exert an effect on the central nervous system to influence and modify behavior, cognition, or affective state. Term includes the following categories: ○ Psychomotor stimulants (for anxiety and depression) ○ Antidepressants ○ Antipsychotics (hallucinations, delusions, paranoia, mood stabilizers) ○ Agents for control of mania or depression (lithium) ○ Antianxiety agents ○ Sedatives, hypnotics or other sleep promoting medications Affect: perceivable action/signs which demonstrate their mood Class of psychotropic medications: Antidepressants: treats depression Antipsychotics: treats psychosis Stimulants: targets problems for those with low concentration, controlling actions, and remaining still or quiet (used for ADHD) ○ ADD - attention deficit disorder (used to be a separate diagnosis) Mood stabilizers: prevents cycling between manic and depression Antianxiety agents: treats signs of symptoms of anxiety Anatomy of the CNS stimulation: Activity is regulated by check and balances system: ○ Excitatory (dopamine, norepinephrine, serotonin) and inhibitory (GABA) neurotransmitters and corresponding receptors in the brain and spinal cord Stimulants act by stimulating the excitatory neurons in the brain (stimulatory ligands to the neurons to control the release and activities of neurotransmitters). Neurotransmitters: Primary monoamines combined with carbonyl group Dopamine: ○ Metabolic precursor of norepinephrine ○ Control of muscle tone and movement (markingson’s) reward, motivation, memory and attention Norepinephrine: ○ Neurotransmitters of sympathetic nervous system ○ Responsible for activity and arousal as well as anxiety learning and pleasure Serotonin: ○ Monoamine neurotransmitter ○ mood, behavior, movement, pain, appreciation, sexual activity, appetite, endocrine secretions, cardiac function, and sleep wake cycle. ADHD low dopamine activity or depression CNS Stimulants: ADHD symptoms: ○ Short attention span, inability to stay still, being impulsive Stimulants may be short acting or long acting: ○ ○ Short acting: fast onset, short duration (15-30 minutes twice a day) Long acting: take longer to act but last longer (once per day for moderate to severe symptoms) Some may need both long acting and short acting to cover school day Long acting in the morning, no stimulants at night time For those with faster metabolism, add a shorter acting one and wears off around 9-10 Stimulants: Short acting: ○ Amphetamine (adderall) ○ Dexmethylphenidate (Focalin) ○ Methylphenidate (ritalin, metadate, methylin) ○ Dextroamphetamine (Dedrine, dextrostat) Long acting: ○ Amphetamine (adderall XR) ○ Dexmethylphenidate (Focalin XR) ○ Methylphenidate (Concerta) ○ Lisdexamfetamine (Vyvanse) (prodrug) Stimulant Use: 2016 CDC: around 9% of children 2-17 6.1 mil have been diagnosed with ADHD ○ Among the children with ADHD, 6/10 were taking ADHD medication ○ Lifetime prevalence of ADHD has been estimated to be as high as 8.1% ○ Methylphenidate. Atomoxetine, amphetamine top 3 of 5 treatments for children under 18 Psychomotor stimulants: Psychomotor stimulants are drugs that produce behavioral activation → behavior activation is usually accompanies by the following: Increased arousal, increased alertness, increased motor activity Acute Effects of Stimulants: Increases in ability to focus/concentration, sociability, libido, mood elevation Euphoria, vigor, decrease the need for sleep, ergogenic effects (Increases in power output) Neurocognitive enhancing effects in healthy individuals Cocaine Schedule II drug - Cocaine derived from the leaves of the coca plant Erythroxylon coca Coca chewing originated in peru ○ Used to sustain the performance of laborers in the peruvian silver mines Travel medicine ○ Utilized in peru to prevent high altitude sickness Once a component of Coca Cola ○ Contained approx 60mg of cocaine per 8 oz serving Initially manufacturing and marketing as “intellectual beverage” and “brain tonic” Cocaine was removed from all beverages in 1903 Mechanisms of action: ○ Less potent than amphetamines but both refer to the dopamine reuptake transporters (DAT) when the presynaptic neuron releases dopamine vesicles into the synaptic cleft. ○ Dopamine will bind to postsynaptic receptors such as D1-D5 either stimulatory or inhibitory. ○ Afterwards dopamine dissociates and is reuptake back into the presynaptic neuron where monoamine oxidase will metabolize it, destroying the dopamine. ○ If cocaine blocks the activity of that, the DAT will be prevented from reuptake dopamine and instead it will bind to the postsynaptic neuron at a different site. Indirect sympathomimetic, not directly binding to receptors, binding to dopamine transporters which indirectly affects level of dopamine. Behavior effects – Cocaine and amphetamines: Recreational doses of amphetamines and cocaine: ○ Enhanced stimulation, coordination and performance ○ Increased strength and endurance ○ Increased mental and physical activation ○ Enhanced performance in simple cognitive tasks Adverse Effects: Because both cocaine and amphetamines bind to the DAT and NAT, there’s an increase in activity of norepinephrine. ○ Increase in BP, heart rate Cardiac effects, increases SBP/DBP 2-14mmHg ○ Decrease glandular secretions ○ Rare: psychosis, mood disturbance, and severe anxiety or panic attacks ○ Adolescents with a history or signs of drug misuse use non stimulant or stimulant with less abuse potential (lisdexamfetamine) in combination with behavior therapy Physiological effects — Cocaine and Amphetamines: Autonomic effects: indirect release norepinephrine and epinephrine ○ Increase systolic and diastolic blood pressure ○ Increased heart rate ○ Bronchial dilation ○ Pupillary dilation ○ Decrease glandular secretions Amphetamines: First synthesized in 1887 in Germany Therapeutics: ○ Treatment of narcolepsy disorders ○ D-amphetamine was sold OTC in Europe until 1960s ○ Methamphetamineis the methylated derivative of amphetamine and was first synthesized in Japan in 1893 ○ The methyl group increases the drug’s ability to cross the BBB (increase bioavailability) Neurons can be demyelinated over long term use Domaine Receptors: All GPCRs w/ 7 transmembrane domains D1-like receptors: Gs coupled (D1 and D5) D2 like receptors: Gi coupled (D2, D3, D4) Therapeutics: L and D isomers of amphetamine: D-amphetamine is more psychoactive ○ Adderall (contains D and L salts in 3:1 ratio) used to treat ADHD and narcolepsy ○ L isomer is still the active ingredient in nasal decongestant inhalers ○ Vicks vapor inhaler Lisdexamfetamine: Dextroamphetamine + lysine group Hydrolyzed to D-amphetamine in the GI tract and it goes to the BBB (prodrug) Therapeutic actions: 13-14 Used for ADHD and binge eating disorder in adults No significant mean changes in systolic or diastolic blood pressure Minor increases in heart rate Similar ADRs as mixed-salt amphetamine and methylphenidate Lower abuse potential Methylxanthines: Caffeine → paraxanthine (84%), theobromine (12%) [in chocolate and stimulatory], theophylline (4%) Trimethylxanthine that antagonized adenosine receptor (slows down heart rate), which lead to downstream secondary effects on multiple neurotransmitters Indirect catecholamine (epinephrine and dopamine) enhancement Mechanism of action: Non-selective inhibition of phosphodiesterase ○ Increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate ○ Adenosine receptor antagonist ○ Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Dosage and effect: ○ Caffeine 100-200mg: decrease in fatigue, increased mental status, alertness ○ Caffeine 1.5g: anxiety, tremors ○ Caffeine 10g: cardiac arrhythmias Use for attention and alertness: Leon (2000) - 19 studies ○ Some benefits of caffeine, and using it was better than providing no treatment at all ○ Decreasing impulsivity, aggression, and parents' and teachers’ perceptions of children’s symptom severity ○ Also compared with methylphenidate/amphetamines Moderate intake can help adults become better able to remain on task Increase speed of reaction time, and enhance the ability to perform complex, intense tasks, like performance in a flight simulator Adverse effects: Cardiovascular effects: positive inotropic, positive chronotropic Diuretic effects: increases the excretion of sodium, chlorine, and potassium Gastric: stimulates secretion of gastric acid Do stimulants inhibit growth? May be related to poor nutrition, lack of appetite, inhibitory effects of increased DA on growth hormones. Evidence varies ○ 2010 prospective study found no association ○ Other studies have demonstrated an association Modafinil and Armodafinil: Treatment for narcolepsy Racemic mixture (modafinil) and as R-enantiomer (armodafinil) Weak inhibitor of DA and NE reuptake transporter but binds to both in vivo at therapeutic doses ○ Requires DA transporter and intact alpha I adrenergic receptors for activity Activities in the locus coeruleus ○ Active orexin-releasing neurons in lateral hypothalamus Pharmacological effects; ○ Armodafinil causes small but significant increase in blood pressure, no sleep rebound, low abuse potential, boosts alertness and performance to levels similar to caffeine ○ ADRs: Headache, nausea, dizziness, insomnia Possible side effects of stimulants: Side effects: decreased appetite, weight loss, headaches, stomachaches, trouble getting to sleep, jitteriness, social withdrawal, tics, sudden repetitive movements or sounds, aggressive behavior or hostility, psychotic or manic symptoms Adverse reactions: ○ Sudden death in children with pre-existing serious heart problems Choosing the initial Psychotropics: Factors to consider in selecting psychotropics: ○ History of prior response (family or family member) ○ Safety in overdose ○ Adverse effect profiles ○ Patient age ○ Concurrent medical psychiatric conditions ○ Concurrent medications (e.g potential for drug interactions) ○ Convenience (e.g minimal titration, once-daily dosing ○ Cost ○ Patient preference Antidepressants: ○ MAO (inhibitors, phenelzine, selegiline, tranylcypromine) ○ Tricyclic antidepressants (amitriptyline, clomipramine, imipramine) ○ Heterocyclic antidepressants (amoxapine, bupropion, mirtazapine) ○ 5-HT-NE reuptake inhibitors (duloxetine, venlafaxine) ○ 5-HT antagonists (nefazodone, trazodone) ○ Selective serotonin reuptake inhibitors (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) Week 7 - Clinical Management of Attention Deficit Hyperactivity Disorder ADHD vs ADD: Attention deficit disorder (ADD) is the odd name for ADHD Officially changed in the 1990s but some people still use both names Definition: A mental health disorder sometimes referred to as a brain disorder or neurobehavioral disorder that includes a combination of persistent problems such as: ○ Hyperactivity (sitting still), inattentive (difficulty paying attention, and impulsive behavior (lacking control) Happens in children and teens, but will continue to adulthood ○ Adult ADHD can lead to unstable relationships, poor work or school performance, low self-esteem, and other problems ○ Usually diagnosed first in childhood and often lasts into adulthood. Children don’t grow out of these behaviors ○ A neurodevelopmental condition with the brain and nervous system that affects attention, impulsivity and activity levels. ADHD Facts: Typical age onset of 3-7 11% of children and 5% of adults More common in males than in females Symptoms may persist into adolescence 68% or adulthood 20-50% Adults with ADHD may be at risks for other psychiatric disorders Potential causes for ADHD: Unknown exact specific causes Genetic components 20-30% ADHD tend to run in families, family studies have identified some genes that appear to play a role in the development of ADHD (Dopamine receptor genes RDR2, DRD4, DRD5, etc). Brain chemicals: these may be out of balance with ADHD (biochemical) Brain changes: areas of the brain that control attention are less active in children with ADHD The brain of people with ADHD: Looks like a behavior problem is actually a brain disorder that affects both structure and function of the brain Research shows that the brain of people with ADHD are smaller in certain areas especially in the frontal lobe, affecting impulse control, concentration, and inhibition Brain development is slower in people with ADHD the neural pathways wont connect and mature at the same rate making it harder to pay attention and focus. This can impair executive function which handles organization and routine tasks Brain chemistry of neurotransmitters in ADHD: Dopamine sends signals throughout the nervous system, helps regulate movement, sleep, emotions, memory, the brain’s reward mechanisms, attention, and learning High dopamine levels may lead to the following symptoms: ○ Hyperactivity, anxiety and agitation, insomnia, delusions, depression, schizo, psychosis. ○ Not to be confused with inattentive and a ADHD diagnosis ○ Unmedicated people with ADHD have a higher concentration of DA transporters. Which lead to lower DA levels in the brain Norepinephrine helps the body respond to stress, involved in mood regulation and the ability to concentrate Noradrenaline high levels cause panic attacks, hyperactivity Low levels cause lethargy, depression, ADHD Affects in the brain: Brain regions smaller in ADHD children: ○ Prefrontal cortex, hippocampus, cerebellum and amygdala. Brain growth of ADHD children catches up to brain growth of normal by late adolescence to early adulthood (matures more slowly) Neurological basis of ADHD: Neuroanatomy: frontal lobes (prefrontal and striatal areas) ○ Neurotransmitters: Norepinephrine, dopamine, serotonin (less degree) Dopamine helps the brain to reinforce rewarding behaviors, norepinephrine affects heart rate, blood vessels, blood pressure and breathing. In the PET scan, the brain of the ADHD patient shows less activity, mainly in the frontal areas ADHD Risk Factors: Some which may affect a baby’s brain development during pregnancy are: ○ Poor nutrition, infections, smoking, drinking, substance abuse, exposure to toxins such as lead Child’s brain development risk factors after birth are: ○ Being born prematurely, toxins exposure, damage or injury to the front of the brain, called the frontal lobe, can cause problems controlling impulses and emotions. Nutritional deficiencies, especially diets low in fiber and omega-e-fatty acids have a greater chance of ADHD Research shows eating too much sugars, watching TV, stressful home life, poor parenting, poor schools, food allergies doesn’t cause ADHD Common symptoms in preschool age: Motor restlessness Difficulty completing development tasks (potty training) Decreased or restless sleep Insatiable curiosity Family difficulties (obtaining/keeping babysitters or preschool placement) Vigorous and often destructive play Demanding Of parental attention, argumentative Delays in motor or language development Excessive temper tantrums (more severe and frequent) Low levels of compliances (especially in boys) Warning signs ages 6-12: Easily distracted Unable to sustain attention Homework is disorganized, sloppy, incomplete, careless errors Blurts out answers before question competed (disruptive) Perception of immaturity Symptoms in adolescent ages 13-18: Excessive motor activity tends to decrease Sense of inner restlessness School work disorganized and shows poorly follow through and fails to work independently Engaging in risky behaviors Difficult with authority figures Poor self-esteem Poor peer relationships, anger, emotional liability Symptoms in adulthood: Highly distractible Disorganized, fails to plan ahead Forgetful, loses things Difficulty in initiating and finishing projects or tasks Misjudges available time, commonly late Makes impulsive decisions ?