PHARMA_PRELIMS.pdf

INTRODUCTION TO PHARMACOLOGY Ibuprofen (NSAID – Nonsteroidal anti-inflammatory FUN FACT! drug) – this is an example of a Generic Name/ Non- Anesthesia – state of being numb proprietary Name/ Brit...

INTRODUCTION TO PHARMACOLOGY Ibuprofen (NSAID – Nonsteroidal anti-inflammatory FUN FACT! drug) – this is an example of a Generic Name/ Non- Anesthesia – state of being numb proprietary Name/ British Approved Name (BAN) Anesthetics – drug used However, there are many identical generic PHARMACOLOGY names in the market because, even though study of drugs/ science of drugs patents grant ownership of these names, the how they affect or interact with the living patents eventually expire. When a patent system expires, the company can choose to renew “Pharmacon” = drugs it, but because renewing patents is “Logos” = knowledge/ study of expensive, they may decide not to. As a DRUG result, once the patent expires and is not renewed, other companies can legally use any substance or chemical that can alter physiologic the same generic name. and psychologic state with the intention to cure Advil & Motrin – Brand/ Proprietary Name has a biologic effect Brand Names – these are catchy and easy “may cure” to remember for marketing purposes, but no excipients they are more expensive than generic According to World Health Organization – any names due to the associated costs. substance used or intended to be used to modify or PHARMACOLOGY IN DENTISTRY explore the physiological system and pathologic Condition: Peptic ulcer and tooth aching/ swelling state for the benefit of the recipient. What drug should you choose? also used to mean addictive/abused substances a. Aspirin – NSAID, for fever, pain reliever, anti- FUN FACT! coagulation Alcohol is considered a depressant. side effect: GIT bleeding Coffee is considered a stimulant. b. Ibuprofen – NSAID MEDICINE fen = anti-inflammatory drug “can cure” c. Acetaminophen – no anti-inflammatory “All medicines are drugs but not all drugs are component medicine” PHARMACODYNAMICS contains excipients – may or may not help curing PharmacoDynaMics = Drug to Man the disease but for marketing purposes “what the drug does to the body” ex. cornstarch and sweetener “dynamics” = power GENERIC NAME VS BRAND NAME drug effects Drug example: mechanism of action one of the main branches of pharmacology PHARMACOKINETICS PharmacoKineTics = Katawan sa Tableta movement of drugs in the body “what does the body do to the drug” “kinesis” = movement ADME Absorption Distribution Metabolism Excretion 1  PHARMACOTHERAPEUTICS application of knowledge about drugs and its cure dose side effects TOXICOLOGY undesirable effect of drug all substances are toxic but the dose or dosage makes it the cure PHARMACY compounding and dispensing of drugs DENTAL PHARMACOLOGY study of drugs or pharmaceuticals typically used in dental field PHARMACOGNOSY study with the sources of drugs derived from plants (one of basic sources) and animal origin – where drugs are derived SOURCES OF DRUGS 1. PLANTS a. alkaloids – basic natural occurring compounds, has 1 nitrogen compound, bitter (e.g. caffeine) b. glycosides – one or more sugar component c. oils – but mineral oil is from petroleum not plant 2. HUMAN e.g. placenta, blood, immunoglobulin (Ig) placenta – maternal exchange of nutrients, for stem cells 3. MICROORGANISMS most antibiotics e.g. penicillin, vaccines (COVID-19) Alexander Flemming – discovered penicillin from penicillium notatum 4. ANIMALS pancreas of pig – insulin for diabetes insulin from pigs are almost similar to humans kaya compatible for type 1 diabetes cod liver oil 2  ROUTES OF ADMINISTRATION VAGINAL OPHTHALMIC Rawt = American NASAL Root = British OTIC a path by which a drug, fluid, or poison, or a 2. ACCORDING TO PHYSICAL FORM substance is brought into contact with the body. SOLID SEMI-SOLID PHARMACOKINETICS LIQUID GASEOUS movement of drug bioavailability of the drug (drug reaches circulation FUNFACT! depending on the route) ANAPHYLACTIC SHOCK INTRAVENOUS ROUTE death due to allergic reaction 100% bioavailable NALOXONE fastest because it bypass other systems antidote for overdosing ex. tablets – dumadaan pa sa hepatic portal vein for further chemical reactions (so mas matagal) EMESIS vomit 1. LOCAL drug applied locally to the skin (topical) ANTIEMETIC ex. paste, powder, lotions, ointments, creams, kontra sa pagsusuka plaster IV, Buccal, Sublingual except Oral 2. SYSTEMIC ACCORDING TO ROUTE ENTERAL ADMINISTRATION oral, sublingual, buccal, rectal (digestive tract) 1. ORAL DOSAGE FORM PARENTERAL taken orally for systemic effect intravenous (30°), intramuscular (90°), ✓ tablets subcutaneous (45°), intradermal (0°-5° ✓ capsules or 10°) ✓ suspensions direct to the circulation ✓ lozenges drug administered through systemic ✓ pills routes is absorbed through the blood ✓ granules ✓ powders DOSAGE FORMS ✓ emulsions ✓ patches refers to the preparation and the physical way in which a substance is presented in the market 2. TOPICAL DOSAGE FORM includes main ingredient from the drug and the drugs applied to the skin or other topical excipients surfaces ✓ ointments TYPES OF DOSAGE FORMS ✓ creams ✓ foams 1. ACCORDING TO ROUTE ✓ gels ORAL ✓ poultice (paste like form e.g. medicinal TOPICAL plants/herbal) RECTAL PARENTERAL RESPIRATORY/INHALATION 1 3. RECTAL DOSAGE FORM 8. NASAL DRUG FORM administered rectally for local rather than aqueous based system that are instilled within or systemic effect sprayed in nasal cavity ✓ solution ✓ spray ✓ suppository (solid but becomes liquid ✓ ointments when inserted and exposed to heat) ✓ suspensions ✓ emulsions ✓ enemas (liquids through anal canals to 9. OTIC DRUG FORM reach and cleanse colons; coffee enema instilled into the ear canal – drug anti-cancer) ✓ solutions/drops – with glycerin or other solvents dispersing 4. PARENTERAL DOSAGE FORM usually sterile, particulate-free, and non- ACCORDING TO PHYSICAL FORM pyrogenic solutions or suspensions (of drugs in water or other suitable physiological acceptable 1. SOLID vehicles) that are injected into the body using capsule syringe and needle granules a. Intradermal (skin test) 0°-5° 2. SEMI SOLID only drop/little amount b. Intramuscular Applied to the skin or to the mucous membrane to achieve local or systemic effect 90° ✓ ointments vaccines ✓ pastes c. Intracardial heart 3. LIQUID d. Intrathecal contains one or more soluble chemical spinal cord substances dissolved in solvents joints ✓ solutions e. Intravenous ✓ emulsions veins ✓ elixir – alcohol and water (ex. cough syrup) 5. RESPIRATORY/INHALED DOSAGE FORM 4. GASEOUS drugs delivered in gaseous, aerosol mist, or ultrafine solid particles into the lungs FUNFACT! ✓ nebulizer ✓ aerosol Alka-Seltzer – antacid tablet 6. VAGINAL DOSAGE FORM NEW DRUG DELIVERY SYSTEMS intended to be used in the vaginal cavity for either contraceptives, induction of labor, 1) IMPLANTS treatment of vaginal infections, or local menopausal symptoms hypodermic tables are placed under the skin by ✓ creams a minor surgery in order to release drugs over a ✓ tablets prolonged period of time ✓ gels and pessaries (any drug intended for extended release for insertion and must liquefy) ex. maintenance, dialysis ✓ suppositories (prepared in cannisters because it is semi-solid then liquefies 2) FILMS & STRIPS due to heat) ex. salonpas ✓ foams ✓ ointments 3) ERYTHROCYTES drug-carrier which helps for the slow release of 7. OPHTHALMIC DRUG FORM the drug into the serum drugs commonly used to treat local ocular disorder like infection or inflammation 2  PHARMACOKINETICS o mas acidic, faster absorption o acidity of stomach enhances once the drug is taken by the patient, what does drug absorption the body (katawan) does to the drug (tableta) pharmaco = drugs MECHANISMS OF kinetics = movement TRANSPORT OF DRUGS drug toxicity will be eliminated if you are knowledgeable in pharmacokinetics how the drugs are carried from the route to the site of action FOUR PROCESSES IN drugs will always pass through membranes PHARMACOKINETICS if may substance sa katawan, from higher to lower concentration (diffusion) 1. ABSORPTION no energy needed (passive) 2. DISTRIBUTION adenosine triphosphate (ATP) needed (active) 3. METABOLISM 4. EXCRETION PASSIVE TRANSPORT a. diffusion ▪ all bodies are not the same, so there are from higher to lower concentration different rates of ADME in accordance with the concentration ▪ regardless, they still undergo the same process gradient (ADME) b. filtration ▪ main organ of elimination = kidney passage through the aqueous solution rate of elimination is affected if there is a pore membranes = size of drug matters kidney problem or disease (larger molecules of drug can’t pass glomerular membrane not healthy = filter through) of metabolites affected water-soluble molecule type of drug ▪ ADME is not the same for everyone because of these factors: health, age ACTIVE TRANSPORT absorption of elderly and pediatric a. carrier-mediated transport patients is slower molecule can’t pass through without a carrier 1. ABSORPTION may carrier proteins – they copy the movement of the drug after administration receptor to act either as an agonist or transfer of drug to the site of action (ex. heart) antagonist regardless of the route to the site of action, a b. facilitated diffusion drug’s effect is related to absorption factors: needs energy solubility of drugs needs unique form of carrier or facilitator o faster absorption if liquid for a specific drug concentration o amount na nagccirculate sa ENDOCYTOSIS dugo a cell can engulf the drug to the site of action o it is impractical to check the like anti-cancer drugs heart for drug concentration kaya ang chinecheck is blood BIOAVAILABILITY (plasma) o ex. illegal drug testing = blood parenteral > oral > rectal > topical and urine surface area (size) fraction of drug that reaches the systemic o gaano kaluwang or kalaki yung circulation following administration nagrereceive proportion of drug that is successfully absorbed vascularity in the systemic circulation o mas maraming blood vessels, however, if acidic drug goes to basic mas mabilis absorption environment (hindi effective/eeffect yung drug) route mas acidic environment, mas mabilis absorption pH 1  ex. site of action: oral tissue (infected = acidic) + anesthesia (basic) = di tatalab IM, SC, ID = rapid IV = immediate/instant FIRST PASS EFFECT/METABOLISM metabolism of a drug during its passage from the site of absorption to the systems/systemic circulation natural process: swallow drug → digestive system → hepatic portal system (initial metabolism, tatanggalin di kailangan) → liver (conjugation, oxidation) → body if the route passes through the first pass effect, it is not bioavailable 2. DISTRIBUTION process of delivering a drug form the bloodstream to the tissues of the body from circulation to different tissues main organ of absorption = mouth FACTORS AFFECTING DRUG DISTRIBUTION 1. plasma/ tissue binding a drug molecule that is already bounded to a tissue, di na makakabalik only free drug is available for drug distribution 2. Blood-brain barrier (BBB)/ placental drugs cannot pass through BBB except other drugs that are developed for the brain or if pregnant for the placenta only lipid soluble or drugs that can dissolve in fats and unionized can cross the BBB 3. Redistribution some drugs are rapidly redistributed ex. inhaler = it is volatile Easier explanation BBB (tindahan sarado) redistribution (pumuntang ibang tindahan) 3. METABOLISM process of biochemical alteration 2 There are two phenomena that happen when a patient takes Clinical Implication: a drug: pharmacokinetics and pharmacodynamics. liver PHARMACOKINETICS main organ of metabolism modification/ alteration of drug happens if not metabolized = drug toxicity ADME deals with safe dosing ELIMINATION KINETICS important to drug prescribers (doctors) bago mafeel ang effect ng drugs need muna mag undergo ng distribution and metabolism 1. First-Order Kinetics then after mapakinabangan, ilalabas ang drug The rate of elimination is proportional to the (elimination/ excretion) plasma concentration of the drug. from the site of action before maeliminate, the As the concentration of the drug decreases, the drug needs to undergo metabolism rate of elimination decreases proportionally. Metabolism – process by which the body The amount of drug eliminated varies with modifies drugs to make them more water- concentration. soluble (hydrophilic) and fat-soluble There is less risk of drug toxicity because (lipophilic), enabling easier elimination, elimination is ongoing as long as the drug is primarily through the kidneys. Some drugs present. are also excreted through the lungs, sweat, Half-life and clearance rate are constant. or breast milk. Most drugs undergo first-order elimination. Phase 1 (Functionalization Reactions): 2. Zero-Order Kinetics Reactions: Involves chemical changes like: The rate of elimination is constant regardless of ✓ Oxidation (adding oxygen) drug concentration. ✓ Reduction (adding nitrogen or removing Even if the dose increases, the amount of drug oxygen) eliminated per unit of time remains the same. ✓ Hydrolysis (breaking bonds with water) If the drug's half-life is unknown and dosing continues, it can lead to adverse reactions due Enzyme: Mainly performed by cytochrome to accumulation. P450 enzymes. Drugs that exhibit zero-order kinetics include Goal: Introduce or expose functional groups aspirin, phenytoin, and ethanol. (e.g., -OH, -NH2) to increase water solubility but Phenytoin (brand: Dilantin) – for sometimes not enough for full elimination. seizures of epileptic Phase 2 (Conjugation Reactions): Reactions: Drug or Phase 1 metabolites are conjugated (attached) to larger, more polar molecules like: ✓ Glucuronic acid ✓ Sulfate ✓ Glutathione Goal: Further increase water solubility, ensuring easier excretion through urine or bile. Summary: Phase 1 modifies the drug’s structure with functional groups. Phase 2 adds a polar molecule for better elimination.  PHARMACODYNAMICS G PROTEIN-COUPLED RECEPTORS intended for drug molecules that need 2nd important to drug developers messenger focuses on the effect of a drug on the body the receptor itself doesn’t make the involves the efficacy and potency of drugs conformational change but rather the 2nd molecular targets = receptors (our body has messenger (e.g. Cyclic adenosine thousands) monophosphate or Camp) outside the site of action = many drug receptors GPCRs are transmembrane proteins that span if a drug is not bound to a receptor, it won’t have the plasma membrane seven times and are an effect associated with G proteins, which include GDP, drug molecule needs a binding receptor to elicit alpha, beta, and gamma subunits → alpha G a response protein dissociates from the beta and gamma extracellular and intracellular domain subunits → dissociation stimulates GDP to transform into GTP (guanosine triphosphate) → MECHANISM OF ACTION OF DRUGS this process initiates a cascade of events where the GTP-bound alpha subunit activates the in normal physiologic processes production of second messengers such as ligand-receptor interaction cAMP, IP3 (inositol trisphosphate), and DAG ligands = drug molecule (diacylglycerol) → wherein these second receptors (GPCR, enzyme-linked messengers activate specific enzymes or receptor): found in cell membrane pathways (cAMP activates protein kinase A drug molecules won’t make another physiologic (PKA), IP3 stimulates the release of calcium ions process but only alter or modify = from the endoplasmic reticulum, DAG activates conformational/ biological change protein kinase C (PKC) → cellular response ex. breathing = improve breathing GDP → GTP (needed to create second receptors are not only on the cell surface messenger) → GTP activates adenylyl cyclase (outside) but also inside the cell (intracellular → Adenylyl cyclase converts ATP to cAMP receptors) (cyclic adenosine monophosphate) → cAMP activates protein kinase A (PKA) → PKA initiates TYPES OF RECEPTOR the cellular response LIGAND-GATED ION CHANNEL when a ligand (drug molecule) binds to the receptor, it causes the gate of the ion channel to open, allowing ions to flow inside the cell this leads to a cascade of reactions within the cell at the end of this process, there is always some form of activation or biological change however, before this biological change occurs, many other processes take place first initial stage/ drug action = binding (extracellular site) → complex processes → next stage/ action = drug effect in normal resting action potentials of cells, there are negative and positive ions that maintain the cell’s homeostatic condition. Ion channels open and close depending on the electrical charges of ions in the extracellular and intracellular fluids. ENZYME-LINKED RECEPTORS AFFINITY has two domains (extracellular and intracellular) tendency of drug to combine with receptor the enzymes involved are kinases → initially, the strength or force of drug to attract a molecule kinases are inactive → upon activation, these the higher the affinity, the more likely the drug enzymes increase their affinity for binding will bind to available receptors, even at lower substrates → the enzymes attach phosphate concentrations groups to tyrosine (tyrosine kinase) residues on Occupancy law of receptor: when more the receptor itself → this process is known as receptors are occupied by the drug, it typically autophosphorylation → the phosphorylated results in a greater biological effect (higher proteins play crucial roles in various efficacy) physiological processes Downregulation/Upregulation: over time, cells may decrease (downregulate) or increase (upregulate) the number of receptors in response to prolonged exposure to a drug, affecting the drug’s efficacy SPECIFICITY refers to the ability of a drug to bind to only one type or a particular kind of receptor. a drug with high specificity will interact only with its target receptor, minimizing unwanted effects on other receptors drugs with lower specificity may bind to multiple INTRACELLULAR RECEPTORS receptor types, increasing the likelihood of side these receptors are targeted by very lipid-soluble effects drugs → these drugs can easily penetrate the cell membrane to reach and bind with DRUG-RECEPTOR RELATIONSHIP intracellular receptors → go inside nucleus to target DNA for transcription process 1. AGONIST most steroids target intracellular receptors agent which activates a receptor to produce an because lipophilic drugs can reach intracellular effect receptors a. Inverse Agonist – agent which activates a receptor to produce an effect in the opposite direction to that of the agonist b. Partial Agonist – activates and produces an effect but not that strong 2. ANTAGONIST no conformational/ biologic change DOSE-RESPONSE RELATIONSHIP a. EFFICACY refers to the maximal response that can be elicited by the drug ability of the drug gaano kaeffective b. POTENCY dependent to dose gaano kalakas the smaller the mg, the more potent the drug is MECHANISM OF DRUG di lahat ng mabisa ay malakas, and di lahat ng malakas ay mabisa !!! drug action → drug effect (after binding) DA – initial combination of the drug DE – the ultimate change in biological function THERAPEUTIC INDEX ADDITIONAL NOTES the safety margin of a drug TI = median lethal dose/ median effective dose when you reach E-max (100%), additional dose Definition: The ratio between the toxic dose will not increase positive effect but TOXICITY. (TD₅₀) and the effective dose (ED₅₀) of a drug Formula: TI = TD₅₀ / ED₅₀ Meaning: A higher TI indicates a safer drug, as there is a larger gap between the effective dose and a harmful dose Example: A drug with a TI of 10 means the toxic dose is 10 times higher than the effective dose, indicating a relatively safe drug THERAPEUTIC WINDOW Definition: The range of drug dosages that produces the desired therapeutic effect without causing significant toxicity. Range: Defined by the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). Meaning: It represents the safe range of doses for a particular drug in clinical use. Example: If the therapeutic window is narrow, small dosage changes can lead to toxicity or ineffectiveness. TOXIC DOSE dose beyond effective dose SAFETY DOSE/ INDEX OF SAFETINESS ED₅₀ divided by TD₅₀ = SAFETY DOSE ED₅₀ - value of drug to produce effectiveness DEPENDENCE a state in which use of drugs for personal satisfaction is accorded a higher priority than other basic needs TOLERANCE the requirement of higher dose of a drug to produce a given response WITHDRAWAL effects when stop using or reduce their intake of a substance  COMBINED EFFECTS OF DRUGS 2. ANTAGONISTIC drug A + B < effect of drug A and B 1. SYNERGISTIC inhibitory drugs drug A + B = increased effect/ response inhibits effects you want to accomplish combination of drug will either increase or a. Physical Antagonism decrease the effect antagonizes itself effect adds up drugs antagonize each other a. Additive through physical interactions drug A + B = increased effect/ kontrahan sila response ex. charcoal adsorbs alkaloids = pinagsama effect prevent absorption drug effects lang nag-aadd up, but b. Chemical Antagonism side effects do not 2 drugs react chemically and form ex. Amlodipine + Atenolol (beta- inactive product blocker) = enhanced anti- ex. tannins + alkaloids = insoluble hypertensive effect; combined tannate synergistic additive effect; and c. Physiologic/ Functional Antagonism higher effect bind to same receptor but opposite b. Potentiation reaction or effect drug A + B > effect of drug A and B ex. histamine and adrenaline combination of drugs has greater ❖ Histamine causes effect than individual drugs bronchoconstriction, while ideal talaga pagsamahin for greater adrenaline causes effect bronchodilation ex. Levodopa + Carbidopa (anti- d. Receptor Antagonism seizure drugs/ anti-Parkinson's receptor mismo drugs) one drug blocks the receptor action dopa – anti-seizure drugs; excess of another drug. or lack of dopamine ex. Anticholinergics oppose the Levodopa contraction of intestinal smooth ❖ prodrug that is inactive → once muscle induced by cholinergic ingested, it is converted into the agonists. endogenous drug dopamine in the body → this increases FIXED DOSE COMBINATION (FDC) dopamine levels in the brain. ❖ Levodopa can cross the blood- pharmaceutical preparations that contain two or brain barrier (BBB), whereas more drugs in a fixed dose ratio dopamine itself cannot cross the ex. Co-Amoxiclav (625mg) BBB. Amoxicillin (500mg) + Clavulanic acid ❖ Levodopa itself is not a drug but (125mg) just activates endogenous drug ❖ Augmentin (brand) → dilate (dopamine). pupil; antibiotic Carbidopa ❖ inhibits the peripheral ex. Neozep (510mg) breakdown of levodopa, Phenylephrine (10mg) + Paracetamol allowing more levodopa to enter (500mg) the brain. ❖ Phenylephrine – treat bronchial spasms or muscle; decongestant 3  ❖ Paracetamol – pain reliever and stomach acidity, leading to heartburn or antipyretic (reduces fever) ulcers. Penicillin G o Kidney Elimination: When liver function mataas first pass effect is compromised, the kidneys may take given I.V. on a greater role in drug clearance. Penicillin V However, if the kidneys are also oral dosage form impaired, this can lead to further issues GTN/ Nitroglycerin/ Glyceryl Trinitrate in drug elimination, increasing the risk of for angina pectoris (chest pain) drug accumulation and side effects. mataas first pass effect genetics stomach pa lang wala na agad psychological factors EMLA/ Eutectic Mixture of Local Anesthetics placebo – no active drug content, often just sugar, but can still produce perceived ADVANTAGES DISADVANTAGES effects based on belief. convenience contraindication to better efficacy one component YOUNG S RULE (AGE DEPENDENT) lesser side effect lack of flexibility in (age/age + 12) x adult dose cost effective dosing (fixed na 12 maximum age ng pedia better patience dosing) compliance costing adverse (allergy) CLARK WEIGHT DEPENDENT) for lbs: (weight/ 150) x adult dose FACTORS MODIFYING DRUG ACTION 150lbs usually weight ng pedia age for kg: (weight/ 70) x adult dose sex race ADVERSE EFFECTS propensity for drug tolerance or intolerance any undesirable/ unintended consequence of can vary based on race and genes drug administration Black people/ African descent – reduced all unwanted effects of the drug response to cardiovascular drugs 1. side effects (propranolol) indirect body weight expected pathological states 2. secondary effects liver cirrhosis → metabolism affected → super infection – overdosing or GERD (can’t drink aspirin because acidic) saturated effects of amoxicillin → kidney elimination dentists are culprit for drug o Liver cirrhosis impairs the liver's ability resistance because every after to metabolize drugs properly. Since the bunot bigay antibiotic liver is responsible for breaking down 3. toxic effects many medications, cirrhosis can cause 4. intolerance drugs to accumulate in the body, leading allergy – nagrrashes pag nagtake to toxicity or prolonged effects. ng drugs o Complications: Patients with liver 5. idiosyncrasy cirrhosis often develop 6. drug allergy gastroesophageal reflux disease 7. photosensitivity (GERD) due to weakened digestion and 8. drug dependence increased abdominal pressure. cross dependence o Aspirin and GERD: Aspirin is acidic and 9. drug withdrawal can irritate the stomach lining. For taper the dose (paonti-onti) → patients with GERD, taking aspirin may because if biglaan, madodoble worsen their condition by increasing symptoms 10. teratogenicity unwanted effects sa fetus 4  first trimester sensitive Chernobyl (1986) – Chernobyl Nuclear Power Plant tetracycline (antibiotic) – if tinatake ng mother during pregnancy and lactation (breast milk) → graying teeth of baby 11. carcinogenicity or mutagenicity cancer causing drugs and other sa genes (gene mutation) 12. drug-induced effects Osteoporosis: A condition sometimes induced by long-term use of certain drugs (e.g., corticosteroids). Aetiology: Study of the causes of such drug-induced effects. WEIGH BENEFIT OVER RISK!! 5