Unit 1. Principles of Psychopharmacology PDF

- Remember the mechanisms in which the cells of the organism communicates - Most medications will act on the receptors by activating, blocking, etc. Neurotransmission The process by which NTs are released by the axon terminal of the presynaptic neuron, and bind to and react with the rec...

- Remember the mechanisms in which the cells of the organism communicates - Most medications will act on the receptors by activating, blocking, etc. Neurotransmission The process by which NTs are released by the axon terminal of the presynaptic neuron, and bind to and react with the receptors on the dendrites of the postsynaptic neuron. The first image shows the steps of neurotransmission, as well as the second image. The image on the right shows the parts of the neurons during synapses: 1. The action potential is propagated over the presynaptic membrane. 2. Depolarization of the presynaptic terminal leads to influx of Ca2+ 3. Ca2+ causes vesicles to fuse with the presynaptic membrane and release transmitter into the synaptic cleft 4. The binding of the NT to receptor molecules in the postsynaptic membrane opens ion channels, permitting an ion flow and initiating an excitatory or inhibitory 3  postsynaptic potential, depending on the specific NT and postsynaptic receptor 5. Excitatory or inhibitory postsynaptic potentials spread passively over dendrites and the cell body of the axon hillock of the postsynaptic neuron, where the summation of these signals determines whether a new action potential will be generated 6. a. Enzyme breakdown (for some NTs like Ach): Enzyme present in the extracellular space breaks down excess transmitter b. Reuptake: of transmitter via reuptake transporters, slowing synaptic action and recycling neurotransmitters for subsequent transmission 7. Neurotransmitters bind to autoreceptors in the presynaptic membrane, helping regulate the release of neurotransmitters by providing feedback to the neuron (negative feedback * Enzymes and precursors for synthesis of transmitter and vesicle wall are continually transported to the axon terminals The image on the right also represents the binding of the NT and the receptors. We need to pay attention to the synapses and the neurotransmission in order to understand the target of some medications and the mechanism of action of pharmacological treatments. The action potential is a nerve impulse; a sudden, fast, transitory, and propagating change of the potential that occurs when the membrane potential of a specific cell location rapidly rises and falls. Depolarization (opposite hyperpolarization) is a change during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is essential to communication between cells. When action potential occurs, there is a depolarization followed by a repolarization. - Depolarization with Ca²⁺ influx is crucial for neurotransmitter release, but depolarization itself primarily involves Na⁺during the action potential. Pharmacological targets The term “pharmacological target” refers to the biochemical entity to which the drug first binds to elicit its effect. There are many entities that can be targeted by drugs, as we can see in blue rectangles on the image (the red arrows point to the pre and postsynaptic neurons and the synaptic cleft). Some psychiatric drugs are NT precursors, that is, molecules that promote the synthesis of neurotransmitters. For example, tryptophan is a precursor of serotonin. We can also administer or chemically alter NTs, alter enzymes of degradation, act on the NT transporters to facilitate reuptake, transform the connections with the receptors (actively deactivate)... We can act on every step of the process, with the aim of changing normal functioning. Elimination of neurotransmitters There are three mechanisms for the removal of neurotransmitter: 1) Diffusion: the NT drifts away, out of the synaptic cleft, where it can no longer act on a receptor 2) Degradation (deactivation): a specific enzyme changes the structure of the NT so it is not recognized by the receptor. For example, acetylcholinesterase is the enzyme that breaks down acetylcholine into choline and acetate. 3) Reuptake: the whole NT is taken back into the axon terminal that released it (presynaptic neuron); NTs are removed from the synaptic cleft so they cannot bind to receptors Pharmacodynamics vs pharmacokinetics There is a double interaction between the drugs and the body. Pharmacodynamics: study of drug disposition in the body, what the drug does to the body Pharmacokinetics: what the body does to the drug ((R)ADME: (release), absorption, distribution, metabolism and elimination/excretion) 4  3. PHARMACOKINETIC PRINCIPLES Pharmacokinetics refers to the movement of the drug once inside of the organism and focuses on the changes in drug plasma concentration. The drugs go through 5 different steps once they are in our body, leading to concentration of the drug in plasma (these 5 steps are called (R)ADME, or (L)ADME in Spanish). ¿How do drugs enter? → Release ¿Where do they go? → Absorption into circulation (rise in plasma concentration) ¿How do drugs move inside? → Distribution to tissues (e.g., brain tissue) (plasma concentration falls) How are they transformed? → Metabolism ¿How do they go out? → Elimination/excretion The drug can be metabolized after distribution, or throughout the whole process, at any point. Steps in pharmacokinetics, leading to concentration of drug in plasma: What does it happen with the drug in the organism? 1) Release The release of the active principle of a medicament when it is included in a pharmaceutical formulation (most cases). ○ It depends on the characteristics of the pharmaceutical formulation. ○ It depends on the route of administration Drugs can also be administered in free form (like IV), where the active ingredient is immediately bioavailable and does not require a release mechanism. Pharmaceutical formulation: is the process in which different chemical substances (i.e., active chemical substances and excipients) will be combined together to produce a medical compound (i.e., medical drug). 5  2) Absorption Absorption of a drug refers to the movement of drug from the site of administration into the bloodstream, and it determines the speed of transmission of the drug to the place of action. The rate of absorption depends on the physical characteristics of the drug and its formulation Single-dose kinetics: ○ Rise in plasma concentration as the drug is absorbed into the circulation ○ Fall in concentration as the drug is distributed to the tissues and eliminated Absorption depends on: ○ Route of administration. For instance, oral intake has the slowest absorption, and IV has the fastest (0 minutes), because the drug goes directly into the bloodstream. Controlled-release patches are faster than other forms too. The route also determines the dose you get at the end. For example, a large amount of medication is lost through the oral route, so the dose needed is higher, but nothing is lost in IV. ○ Pharmaceutical formulation (release) ○ Physico-chemical properties of the drug (lipids, proteins, pH, solubility, etc.) ○ Transporter mechanisms ○ Physiological factors: age (children need reduced doses, food content for oral route, etc.) ○ Pathologies (ex: liver or kidney diseases) ○ Iatrogenic (ex: other medicaments) Routes of administration Oral (the slowest absorption rate, first-pass effect) Intravenous (fast rise in concentration, absorption = 0) Intramuscular (slower〜 absorption, 30 min) → injected into muscles Subcutaneous (15-30 min absorption; i.e. insulin) → injected under skin Intraperitoneal (medium absorption speed) → injected into abdominal cavity Rectal (rapid absorption but poor control of dose, reduced first-pass effect) Topic (slow absorption and poor control of dose)/transdermic → applied to skin Sublingual: dissolving the drug under the tongue (fast, absorption by veins under the tongue and drug reaches directly the heart and cave vein, no first-pass effect) Intrathecal, epidural: avoidance of blood-brain barrier → directly administered into the spinal region or CNS (not requiring systemic absorption as it’s directly applied to the cerebrospinal fluid (CSF) within the spinal canal) Others: ocular (eye drops), intranasal (nose, fast absorption), etc. There are enteral and parenteral routes of administration. Enteral routes are those that use the gastrointestinal pathway: oral, sublingual and rectal. The rest are parenteral. Bioavailability As we have mentioned before, the route of drug administration affects the bioavailability of a drug and thus influences the dosage. Bioavailability is, given a specific dose, the fraction of the active drug that reaches the systemic circulation (bloodstream). It refers to the rate of absorption (i.e., if 100 mg are administered and 70 mg are absorbed without modification, then the bioavailability (BD) is 70%). The bioavailability of a drug administered intravenously is 100%. When a medication is administered via other route (such as orally), its bioavailability generally decreases, due to incomplete absorption and hepatic first-pass metabolism. - Bioavailability is usually going to be smaller than the amount of the dose because we lose components and it takes a lot of time. Ex: when taking a pill of paracetamol you need time in order to absorb it and feel analgesia, but by intravenous the effect is felt right away. The bioavailability may vary from patient to patient. Bioavailability is one of the principal pharmacokinetic properties of drugs, and must be considered when calculating dosages for non-intravenous routes of administration. 6 First-pass effect The first-pass effect or first-pass metabolism is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during absorption, generally related to the liver and gut wall. Notable drugs experience a significant first-pass effect: morphine, diazepam, lidocaine, imipramine, buprenorphine, midazolam, etc. This first pass through the liver greatly reduces the bioavailability of the drug. After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver is the main organ in metabolism. It metabolizes many drugs; and sometimes only a small amount of active drug emerges from the liver to the rest of the circulatory system. Bioequivalence The bioequivalence is the absence of a significant difference in the rate and extent to which a drug becomes available at the site of action when administered at the same dose under similar conditions. Two pharmaceutical compounds are bioequivalents when their bioavailability and the time they reach the maximal plasma concentration are similar (i.e. absorption is similar and are therapeutically equivalent). Bioequivalence is important in order to switch medications. In the following graph, A and B (blue and red) are bioequivalent. We can see that maximum concentration is reached for both A and B just after administration (so they are IV). Two or more chemically or pharmaceutically equivalent products produce comparable bioavailability characteristics in any individual when administered in equivalent dosage regimen (parameters compared include the area under the plasma concentration versus time curve (AUC) from time zero to infinity AUC, maximum plasma concentration and the time of peak concentration). The graph shows the pharmacokinetic parameters describing the plasma concentration-time profile of an orally administered drug. Monitoring the therapeutic range helps in adjusting dosages to maintain effective drug levels while minimizing the risk of harmful side effects. Brand Versus Generics Brand medications are those whose patent (which lasts 20 years) is owned by the pharmaceutical company. After these 20 years, any company can synthesize a bioequivalent of that medication. Generics are cheaper because the companies that produce them do not have to pay for the patent. - Generic medications are designed to be bioequivalent to the brand-name drug. This means they have the same active ingredient, dosage form, strength, and route of administration, and they provide the same therapeutic effect. While generics may differ in color, shape, or inactive ingredients (such as fillers or flavorings), these differences do not affect the drug’s efficacy or safety. Examples of non-bioequivalent products: Digoxin. Doctors in Israel noticed 15 cases of digoxin toxicity between Oct/Dec 1975 with almost no reports for the same period the previous year. It was found that the local manufacturer had changed the formulation to improve 7  dissolution without telling the physicians. Urinary data suggested a two-fold increase in availability of the new formulation. Phenytoin. One report described an incidence of Phenytoin intoxication in Australia in 1968- 1969. Apparently the tablet diluent was changed from calcium sulfate to lactose. Later studies showed that the bioavailability was higher from the dosage form containing lactose. ○ Formulation differences: small differences in inactive ingredients (e.g., fillers, binders) or changes in the drug's formulation can affect the rate and extent of drug absorption. Even minor changes can lead to significant variations in drug levels in the bloodstream Other drugs with problems in the past include Acetazolamide, Aminosalicylate, Ampicillin, Aspirin, Ascorbic Acid, Chloramphenicol, Chlorothiazide, Diazepam, Furosemide, Iron, Levodopa + 10 (Gibaldi, 1984) Pharmaceutical formulation Ordered from slowest to fastest rate of absorption: Solid (pills, tablets, capsules, suppository...) Semisolid (pomades, creams..) Liquids (suspensions, injectables, syrup...) Gas (aerosols, vaporizators...) Physico-chemical characteristics of drugs Liposolubility/hidrosolubility (if it is soluble in water or in lipids) Polarity pH (ionization) Size (smaller usually easier absorbed) These aspects determine how the drug is absorbed: how it interacts with the cell membranes, how it enters the cells, etc. A drug passes through the cell membrane more easily when it is not ionized (positively or negatively charged). ○ Most drugs are weak acids or weak bases (the strongest acids have a pH of -1, the strongest bases have a pH of 15 and the neutral pH is 7). pH determines the grade of ionization of molecules (affecting their ability to cross cell membranes). Transporter mechanisms Passive diffusion or transport: in favor of concentration gradient. A type of transport that does not require energy to move substances across cell membranes. Instead of using energy, like active transport, it relies on the concentration gradient: molecules/substances tend to move from locations of high concentration to one of low concentration. Facilitated transport or diffusion (molecules): spontaneous passive transport of molecules across a membrane via specific transmembrane integral proteins. It does not directly require chemical energy; rather, molecules and ions move down in favor of the concentration gradient. 8  (as passive diffusion). Facilitated diffusion differs from simple diffusion in several ways: ○ The molecules bind to the membrane-embedded channel or carrier proteins. Carrier proteins are proteins found on the membrane, so molecules can get through the membrane via these proteins. ○ Facilitated diffusion is saturable. This means that, if the concentration gradient of a substance is progressively increased, the rate of transport of the substance will increase up until it reaches a point where all the carrier molecules are occupied. As there is a limited number of carriers in the membrane, further increases in the gradient will produce no additional increase in rate. When the concentration of the transported substance is raised high enough, all of the carriers will be in use and the capacity of the transport system will be saturated. ○ There is competitive inhibition. Competitive inhibition occurs when a substance competes with the substrate for binding to the same active site on the carrier protein or channel. Active transport: the movement of molecules across a cell membrane from a region of lower concentration to a region of higher concentration, so against the concentration gradient. It requires cellular energy (molecules of ATP) in order to produce movement against the concentration gradient. Active transport is also saturable, and there is competitive inhibition. Endocytosis: a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested Physiological factors (age, food content for oral route, etc) - Gender is essential. The majority of studies in pharmacology haven’t been taking care of gender, focusing just on males, which is a mistake due to the different biology between sexes, so medication can act differently. Pathologies (i.e., liver or kidney diseases) Iatrogenic (i.e.other medicaments) - We don't know the mechanisms very well, but we know there are interactions. 3) Distribution It refers to the process of a drug leaving the bloodstream and going into the organs and tissues. Volume of distribution (VD) or apparent volume of distribution of a drug: the degree to which the drug is distributed in body tissues versus the plasma. It indicates the distribution of a medication between plasma and the rest of the body after enteral or parenteral dosing (a higher VD indicates a greater amount of tissue distribution). VD is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma. VD = drug dose/C0 C0 = plasmatic concentration at time = 0 Distribution depends on: Physico-chemical properties of drugs: polarity, liposolubility/hidrosolubility Membrane permeability Vascularization of tissues. The pharmacokinetic two-compartment model divides the body into central and peripheral compartments, with different levels of vascularization. 9  ○ Central compartment (compartment 1) consists of the plasma and tissues where there is good vascularization and the distribution of the drug is practically instantaneous: heart, lungs, kidney ○ Peripheral compartment (compartment 2) consists of tissues where vascularization is bad and the distribution of the drug is slower: bones, skin, adipose tissue Anatomo-functional characteristics of tissue Binding to plasmatic proteins: ○ Drug-protein complex: If the drug is bound to a protein, forming a drug-protein complex, it is retained in the capillaries due to its big size. ○ Free-drug: If it is not bounded, the free-drug is smaller and diffuses to the tissues and binds to the receptors to act pharmacologically. The picture shows that only free drugs (not bound) can get through the tissues (sometimes they do) Three pharmacological compartments of drug distribution The characteristics of the different compartments determine and affect how the drug enters and acts on those compartments. - Distribution refers to the organ of the brain but also to the compartments of it. Plasmatic/intravascular: high molecular weight, binding to plasmatic proteins. Drug is too big to go out from endothelial junctions of capillaries and stay in the vascular compartment (i.e., heparin). Extracelular: low molecular weight, hydrophilic (polar). Drug is able to release the capillaries and goes to the interstitial liquid, but is not able to go inside the cells (i.e., antibiotics). Intracelular: low molecular weight, lipophilic (non-polar). Drug enters the tissue and goes through the cell membranes to the intracellular liquid (i.e., ethanol). 4) y 5) Elimination Elimination of a drug from the blood relies on two processes: Biotransformation (metabolism) of a drug to one or more metabolites, primarily in the liver and the excretion of the parent drug or its metabolites, primarily by the kidneys. 4) Metabolism The biotransformation or metabolism is the chemical transformation of the drug needed for activity/inactivation or to be excreted. ○ Metabolism is essential both for activating drugs that need conversion to become effective and for inactivating drugs to ensure they are safely removed from the body. The majority of hydrophilic drugs are excreted with no biotransformation. Lipophilic drugs are biotransformed into more polar (hydrophilic) compounds to be excreted (not absorbed by renal tubules in the kidney) 10  Tissues where metabolism takes place: liver, kidneys, gut, plasma, heart, brain… ○ Every cell in the organism metabolizes drugs Results of the biotransformation of drugs: Inactivation of the drug Activation of the metabolite(s) of an active drug Activation of an inactive drug (prodrugs, active metabolites) A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug First Pass-Effect: Tablets of morphine are administered in higher doses compared to IV morphine. This is due to the presystemic metabolisms or first-pass effect. Phases of drug metabolism: There are three phases: 1) The lipophilic drug is transformed into a soluble metabolite, often active. This may occur by oxidation (loss of electrons or an increase in the oxidation state), reduction (gain of electrons or a decrease in the oxidation state) or hydrolysis (when a molecule of water breaks one or more chemical bonds). This process is catalyzed (metabolized) by cytochrome (CYPs) enzymes. 2) The soluble metabolite is transformed into a highly-hydrosoluble metabolite, usually inactive. The chemical reaction that causes it is conjugation. These reactions are catalyzed by a large group of transferases, mainly glutathione S-transferases (GSTs) and also UDP-glucuronosyltransferase (UGTS). 3) After phase II, substances may be further metabolized. Conjugates (products from phase II) and their metabolites can be excreted from cells through multidrug resistance protein 1 (MDR1), transporter proteins of the cell membrane that pump substances out of cells. As we have seen before, these phases correspond to elimination (metabolism + excretion). There may be drug interactions (that is, a drug that inhibits or induces the enzyme that degrades other drugs) in phase I and phase II. Due to shared metabolic pathways, protein binding, transport systems, enzyme induction/inhibition, physiological effects, etc. Hydrophilic drugs do not need biotransformation and are excreted without transformations (some drugs go directly to phase II of metabolism). Lipophilic drugs need to be converted in more polar (hydrophilic substances) and to conjugate with compounds in order to be eliminated 5) Excretion Kidneys are the main organs that participate in the elimination, but it depends on the pathway. Drug excretion pathways: (plus others such as tears, breast milk, hair...) The main drug excretion pathways are the following: 11  4. PHARMACODYNAMIC PRINCIPLES Pharmacodynamics is the study of the drug mechanism of action: what the drug does to you. It studies from drug concentration in plasma to drug concentration at the site of action, usually at cellular level, where the physiologic drug effect is exerted. Drug-receptor interactions: The binding of a drug to a specific receptor may modify directly or indirectly different biochemical processes in the cell. Molecules that bind to a receptor are called ligands. Binding depends on chemical structure. Receptors and ligands come in many forms; a receptor recognizes just one (or a few) specific ligands, and a ligand binds to just one (or a few) target receptors. Binding of a ligand to a receptor changes its shape or activity, allowing it to transmit a signal or directly produce a change inside of the cell. The effect of the drug is only produced if said drug has an appropriate shape in order to bind to a specific receptor. Pharmacological targets: There are different types of receptors, the major receptor groups are: Ion channels: can open in response to the binding of a ligand and allow ions to pass through the membrane G-protein coupled: cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are also called seven- transmembrane receptors because they pass through the cell membrane seven times (see image). Enzymatic cytosolic domains: the binding of the ligand causes enzymatic activity Intracellular receptors: located on the inside of the cell, typically cytoplasm or nucleus, rather than on the membrane Drug-receptor interactions: The biological activity of a drug depends on: Affinity: the degree to which a drug binds to its receptor → binding probability Selectivity: few drugs are absolutely specific for one receptor. Selective drugs bind to very limited types of receptors, and non-selective drugs bind to several types of receptors → how easily NT binds to receptors Intrinsic activity or efficacy: the ability of a drug-receptor complex to induce a maximal pharmacological response Efficacy relative to endogenous agonist: An endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. For example, the primary endogenous agonist for serotonin receptors is serotonin. An agonist is a drug that binds to the receptor, producing a similar response to the intended chemical. An antagonist is a drug that binds to the receptor, either on the primary site or on another site, and stops/blocks the receptor from producing a response. 12 Types of ligands: - Inverse agonists reduce the receptor's activity below its baseline level. if a receptor normally produces a level of activity (e.g., excitatory), an inverse agonist would decrease that activity, but not necessarily flip it to inhibitory. - In systems where too much excitation is harmful (some mental disorders), a partial agonist provides a balanced activation, prevents overactivation but still triggers some receptor activity. They offer partial receptor activation compared to full agonists. - Receptors and their effects (excitatory or inhibitory) are not always fixed and depend on the receptor subtype, tissue, and situation. Dose-response curve: The response to a drug concentration is complex and nonlinear. Dose-response data are typically graphed with the dose in the x-axis (in logarithms) and the measured effect (response) on the y-axis (therefore, it is a semi-logarithmic graph). Potency: refers to the amount of drug required to elicit a pharmacological response. It is proportional to affinity and efficacy. Potency is measured by ED50 (dose of drug that induces the 50% of the maximum effect). ○ High potency does NOT mean more therapeutically effective or more clinical efficacy ○ In order to compare potency, the drugs must produce the same therapeutic effect. ○ For example, you can't compare the potency of a medication used for pain relief with one that lowers blood pressure. ○ A more potent drug will require a smaller dose to achieve the desired effect (or obtain the maximum pharmacological effect) than a less potent drug. ○ Drugs with a lower E50 are more potent than drugs with a high E50. The lower the ED50 (Effective Dose 50), the stronger the drug is at a lower dose. ○ The drug of the red curve is more potent than the blue one, because a lower dose is needed to get the same effect → more in the left more potency ○ ED, therefore, is the value of the x-axis that corresponds to a response of 50% ○ The most potent drug between two is the one that increases and reaches a high response/effect before, with a lower dose (lower x-value). 13  - More efficacy higher pharmacological effect → taller slope Administration of several drugs: The effect can be additive or synergic: - Additive effect: A+B → the final effect equals the effect of A + effect of B - Synergic effect or potentiation: >A+B → the final effect is different or higher than just the sum of A + B - Synergic effect happens because the drugs interact in a way that enhances each other's actions such as: targeting different receptors, enhancing absorption or metabolism, amplifying biological effects, reducing inhibition, etc. ○ Effective dose ED50: dose that induces half of the maximal effect ○ Toxic dose DT50: dose that induce toxic effects in 50% of users ○ Lethal dose DL50: dose that induces mortality in 50% of users (determined only in animals or people that committed suicide) Side Effects Undesirable or adverse effects at therapeutic doses. Toxic effects by intoxication or overdose are not considered. We need to know the risk/benefit balance to see if that medication is worth it Therapeutic range: margin of safety in which the drug induces beneficial effects but not undesirable toxic effects - Example: Morphine (medication to control the pain) taken in several doses apart from blocking pain, it can aslo block the respiratory system, which could be deadly. MEDICATION DEVELOPMENT - Practice 1: Drug Development There are five steps in the process of developing a medication: 1) Discovery and development 2) Preclinical research 3) Clinical development 4) FDA review. Food and Drug Administration, a team that thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve it 5) Post-market monitoring 14 First, animal models are used: In order to know the behavioral pharmacology of psychoactive drugs o To know the neurochemical mechanisms To develop and evaluate medications This is the preclinical phase (phase 0) or basic research Then, clinical trials are carried out: These are the phases I, II, III and IV of medication development Safety – Efficacy – Security - Surveillance (FDA approved) are tested, in that order The number of compounds studied are greatly reduced as we go from one phase to another. First, during the drug discovery, 5000-10000 compounds are considered. In the pre-clinical trial, around 250 are studied. During the first 3 clinical trials, only around 5 compounds are considered, and after the FDA review, only 1 compound is produced and commercialized. In phase 1, there are 20-100 volunteers; 100-500 in phase 2; and 1000-5000 in phase 3. Pharmacovigilance The following agencies or services study and approve medications: Food and drug administration (FDA) European medicine agency (EMEA) Sistema español de farmacovigilancia (SEFV) Agencia española de medicamentos y productos sanitarios (AEMPS) They study safety (the toxicity and the relationship between risks and benefits), the efficacy (the beneficial effects) and the security (the quality and minimal purity). Example: Notas de Farmacovigilancia. Hiperglucemia con los antipsicóticos atípicos. Comisión de Farmacia y Terapéutica. Drotrecogina alfa activada. CLASSIFICATION OF PSYCHOACTIVE DRUGS Psychoactive Drugs They cross the blood-brain barrier They target the brain and alter brain function by influencing neurotransmission Produce changes in behavior, cognition, emotion and subjective experience They can have medical or recreational uses 15 Pharmacological targets: Examples: 5-HT: antidepressants, antimigraine agents, anxiolytics, antiemetics... DA: antipsychotic, antiparkinson agents, amphetamines, cocaine… NA: antidepressants, antihypertensive… Ach: nootropics, cognitive enhancers, antiparkinson’s agents... PLACEBO AND NOCEBO EFFECT: Placebo effects: Basic mechanisms and clinical applications - Klinger R. (2014) Nocebo effects can make you feel pain - Colloca L. (2017) The human phenomenon that better reflects the inseparable interaction between psychological and somatic factors is the “placebo effect“. Together with expectancy theories, classical conditioning has been discussed as being a major explanatory model. Other learning principles, such as social learning (via vicarious reinforcement), are also thought to play an important role. In evolutionary terms, nocebo and placebo effects coexist to favor perceptual mechanisms that anticipate threat and dangerous events and promote appetitive and safety behaviors. From a neurobiological viewpoint, research findings have revealed the involvement of cortical, subcortical and recently spinal structures in the placebo-induced modulation of pain that cognitively triggers the release of endogenous opioid and non-opioid substances. Nocebo (and placebo) effects involve neural circuits in the CNS that modulate the perception of touch, pressure, pain, and temperature. All pain treatments consist of a verum component (active pharmacological component) and a placebo component. Placebo treatment is associated with expectancy, fear, previous experiences with clinical staff and co-interventions, but also illness-related factors and personality variables. Optimism, suggestibility, empathy and neuroticism (=emotional reactivity, vulnerability to mental disorders like anxiety and depression, and high sensitivity to threat) have been linked to placebo effects, while pessimism, anxiety and catastrophizing have been associated to nocebo effects. A study found that motivation and suggestibility accounted for the 51% of the variance in the placebo responsiveness, and anxiety severity, openness-extraversion and depression accounted for the 49% of the variance of the nocebo responses (this is not a consequence of expectations, as it was tested that expectations did not affect personality factors and personality did not affect expectations). Besides, placebo effects are also stronger if patients suffer from chronic, stress-related conditions and if the treatment is delivered by someone in whom they have confidence. To address the placebo effect effectively in clinical applications, focus on improving elements of the clinical encounter and strengthening the patient-physician relationship. Enhancing aspects such as verbal encouragement, positive attitudes, and addressing emotional needs. While it is essential to avoid deception, integrating the placebo effect can optimize the efficacy of actual treatments. This approach does not replace effective medications but rather complements them by enhancing their overall impact. Current research supports the use of placebo effects in clinical settings, emphasizing the need for ethical application and consideration of individual patient factors. Incorporating strategies to boost placebo responses, based on their underlying mechanisms, can offer new opportunities for improving treatment outcomes and patient care. Some studies show that the placebo effect can be enhanced by verbal manipulations, prior experience with treatments, attitude, expectations and emotional feelings. Plus, it’s the base of homeopathy (medications with little chemicals and effectiveness). Patients that receive placebos often report side effects (nocebos) that are similar to those experienced by patients that receive the actual drug. Similarly, informing patients that a treatment has been stopped, compared to a covert treatment interruption, alters the response to morphine, diazepam, or deep-brain stimulation in acute pain, anxiety, or Parkinson’s disease, respectively. Patients informed about the interruption of each intervention experience a sudden increase of pain, anxiety, or bradykinesia, also respectively. Thus, communication of treatment discontinuation might, at least in part, lead to nocebo effects with aggravation of symptoms. Treatment changes influence patients’ expectations of improvement, which in turn affect their depressive symptoms. Nocebo effects can influence patients’ clinical outcomes and treatment adherence. In the same way, misleading information about side effects via public claims has led to treatment discontinuation and an increase in fatal strokes and heart attacks. Literature suggests that placebo and drug do not involve separate processes, one psychological and the other physical, that add up to the overall effectiveness of the treatment; rather, they may both operate on the same biochemical pathway: the one governed in part by the COMT gene. 16