KNES 372 FINAL

what is a drug?

any substance other than a normal constituent of the body or one that is required for normal bodily function, that when applied to or introduced into a living organism has the effect of altering bodily function

what is pharmacokinetics?

study of the time course of a drug and its metabolites in the body after administration by any route (what drug does to the body as its administered) 

what are the different components of pharmacokinetics?

absorption (how drugs get into the body), distribution (how it goes to different parts of the body), metabolism (biotransformation, how its transformed by the body), excretion

what are the routes of administration in absorption?

oral, sublingual/buccal, inhaled, topical (eyes, ears, nose, skin), vaginal and rectal (mucosal membrane), transdermal, injection (IV, IM, SC, IA)

what are the characteristics of oral administration in absorption?

most common, large surface area for absorption in the gut which can get affected by GI secretions, may not be completely absorbed 

what are the characteristics of buccal/sublingual administration in absorption?

cheek or under the tongue, bypass effect of liver directly intoo the bloodstream

what are the characteristics of vaginal/rectal administration in absorption?

use mucosal membrane

what are the characteristics of injections administration in absorption?

more common in sports medicine

what are drug factors in absorption?

formulation (aerosol - slow release allowing substance to be in bloodstream for longer and slower rate, tablet, liquid, delayed release), solubility (lipid vs water), particle size, pH, drug ionization (ionization = slow)

what are host factors in absorption?

motility of gut (inflammation decreases time for absorption), food in stomach slows things down, vomiting/diarrhea, circulation to the site of administration and surface area at site of administration, degree of first pass metabolism 

what is bioavailability?

fraction of the dose administered that reaches the systemic circulation in an unchanged state, first pass effect

what are the steps in the first pass effect?

drug is taken orally, drug enters GI tract, active drug is absorbed from stomach and small intestines, high blood concentration of drug is in hepatic portal vein, low blood levels after passing through liver

what are the different methods of drug transport?

diffusion (passive, lipid soluble), facilitated diffusion (membrane protein, polar molecules, takes more time), active transport 

how can drugs be distributed in the body?

plasma, interstitial fluids (between cells, not really active), intracellular fluids (into cells, active), transcellular fluids (CSF, peritoneal fluid, pleural), fat

what are the patterns in tissue distribution with drugs?

first place drug goes is brain, heart, and kidneys (can take hours to get to muscle)

what are the categories of factors affecting distribution of drugs?

mechanical, biochemical

what are the mechanical factors affecting distribution of drugs?

blood flow, barriers (BBB, placenta)

what are the biochemical factors affecting distribution of drugs?

lipid solubility, binding to plasma proteins (albumin, glycoproteins), accumulation in tissues (depots, fat), pH (affects where certain drugs can go)

what is the function of metabolism in biotransformation?

conversion by enzymes to more polar (less lipid soluble) forms, allows easier elimination (typically by kidneys)

where does metabolism occur and what are the stages?

occurs in smooth ER of cells in liver, in kidneys, GI tract, lung, and plasma, consists of Phase I and II reactions

what can drugs become through metabolism?

activated (from pro drug to drug, codeine to morphine), changed to another metabolite, changed to toxic metabolite, inactivated

what is the phase I in metabolism?

Cytochrome P450, conversion to polar metabolite (oxidation, reduction, hydrolysis)

what is the phase II of metabolism?

conjugation, coupling of drug (or its polar metabolite) with an endogenous substance, usually helping with transfer out of the body

what are some factors affecting metabolism?

genetic (mutation in genes, protein alteration), environmental (enzyme induction or inhibition, drug interactions), physiological (age, liver disease-cirrhosis, renal disease-diabetic or hypertensive nephropathy, nutrition - poor intake less robust protein, alcohol-short term limit to break things down, smoking)

how are drugs typically eliminated?

kidneys (primary), GI tract, exhalation, saliva 

what is half life?

time taken for the serum drug level to fall 50% during elimination

what is first order kinetics?

5 half lives to reach steady state

what is zero order kinetics?

where concentration of drug doesnt matter, see constant elimination rate’

how does drug administration and distribution differ in kids and adults?

smaller distance in kids, different ability to expel and metabolize, consider longest exposure they can withstand or require for treatment 

what is meant by pharmacodynamics?

physiological effects of drug on the body, activation or blockage of cellular receptors, signal messaging

what are the different drug effects?

agonists (increases activity of enzyme, up regulate, full or partial), antagonists

what can antagonists act as?

chemical (chelation, remove substance from ability to interact with others), functional (acting independently at different receptors and have opposite physiological effects), competitive inhibitor, non-competitive inhibitor

what is a therapeutic window?

concentration of drug that produces desired effect

what is meant by the lower limit of a therapeutic window?

concentration that produces half the greatest possible effect

what is meant by the upper limit of a therapeutic window?

no more than 5-10% of patients experience a harmful side effect

what is meant by ED 50?

effective dose, dose that gives the required response in 50% of subjects

what is meant by TD50?

toxic dose, dose that produces harmful side effects in 50% of subjects 

what is therapeutic index?

TD50/ED50, reflects margin of safety, larger=safer

what are some adverse drug reactions?

overdose toxicity, side effects/sensitivities within therapeutic window (diarrhea from antibiotics, sedation from anti-histamines), allergic reactions, drug interactions 

what is meant by overdose toxicity in ADRs?

taking a drug above its therapeutic range, can produce respiratory depression

what is meant by allergic reactions in ADRs?

drug acts as an allergen/antigen, immune response

what is meant by drug reactions in ADRs?

naloxone (competitive inhibitor), inducing or inhibiting liver enzymes

what are the characteristics of alcohol absorption?

ethyl alcohol/ethanol absorption, occurs in GI tract by simple diffusion (small size), 70-80% duodenum and jejunum, delayed if food in stomach

what are the characteristics of alcohol distribution?

areas with high blood flow rapidly reach equilibrium (brain, heart, lungs, liver), 4% into fatty tissues, volume of distribution less for women than men (lean body mass)

what is the process of alcohol metabolism?

metabolized in liver (first pass effect), alcohol dehydrogenase, different variations in amount of ADH for each person, oxidation occurs in mitochondria, aldehyde dehydrogenase, acetate released to blood oxidized to CO2

what are some genetic variations that can impact alcohol absorption?

alcohol dehydrogenase can operate 5X normal, aldehyde dehydrogenase 2 deficiency

what are the characteristics of alcohol dehydrogenase acting at 5X normal in alcohol absorption?

acetaldehyde accumulates (larger spike) resulting in vasodilation, facial flushing, bronchospasm (muscles around lung), and tachycardia, 85% asian populations, 5-10% english, 20% swiss

what are the characteristics of aldehyde dehydrogenase-2 deficiency in alcohol absorption?

increases acetaldehyde, 50% asian populations, can’t convert to acetate as quickly/readily

what is alcohol elimination? How does it work?

principle elimination by oxidation to Co2 and H2O (urine- <1%, lungs 1-3%, liver oxidation 90-95%)

what are the clinical effects of alcohol elimination?

stimulant at small doses, CNS depressant at higher doses, diuretic, toxic effects on muscle, heart, brain (cerebellum), liver

what are the different amounts of alcohol elimination and what are the effects?

50-100 (incoordination), 150-200 (decreased reaction time), 200-300 (nausea, vomit, ataxia), >400 (coma, respiratory failure, death)

how can we avoid alcohol intoxication?

eating slows absorption, slow down dose, having higher lean body mass, genetics

what is the purpose of therapeutic drugs in sport?

facilitate rehab, reduce inflamamtion and pain

what is acetaminophen?

tylenol, paracetamol (para-acetylaminophenol), possible acton through COX centrally (temperature effects), serotonin (5HT), modulation of endogenous cannabinoid system 

what are the effects of acetaminophen?

analgesic and anti-pyretic (fever reducing), ceiling effect-1000mg per dose (liver damage around 7000mg)

what are the pharmokinetics of acetaminophen?

high absorption in SI, metabolism in liver (glucuronidation, sulfation), time to peak (10-60mins), half life (2-3 hours)<elimination through urine mostly as metabolites, overdose (depletes liver of glutathione which detoxifies metabolic intermediaries)

what are NSAIDs?

nonsteroidal anti-inflammatory drugs, salicylates and related compounds, anti-inflammatory, anti-pyretic, anti-platelet and analgesic, act by inhibiting cyclo-oxygenase (COX)

what do most NSAIDs affect?

COX I and II

what is COX I?

cytoprotective prostaglandins (protect gastric mucosa, aid platelet aggregation)

what is COX 2?

inflammatory prostaglandins (recruit inflammatory cells, sensitize skin pain receptors, regulate hypothalamic temperature control)

what are the pharmacokinetics of NSAIDs?

absorbed rapidly from the stomach and upper SI, peak time (1-2 hours), distribution throughout most body tissues, metabolized in liver, excreted through urine, half life (2 hours)

what are the side effects of NSAIDs?

stomach (nausea, pain, gastritis, ulcer/bleeding), kidneys (hypertension, fluid retention, renal failure if too long and too high dose), vessels (vasoconstriction-hypertension), other (tinnitus-ringing in ears sometimes due to aspirin)

what can NSAIDs do? What are the implications in injury?

inhibit of protein synthesis and muscle repair/regeneration, inhibit tenocyte proliferation and collagen formation but may be useful in acute/reactive tendinopathy, may impair bone healing in callus/end of healing time but no evidence

what are some topical NSAIDs and what is the purpose?

diclofenac (voltaren), indomethacin, ketoprofen, avoids systemic effects (<5% plasma concentration of oral form)

what are the steroids used in sports?

anabolic, glucocorticoids/corticosteroids/cortisone (produce endogenously within adrenal cortex from cholesterol, main form is cortisol-hydrocortisone, reduce pain and inflammation, inhibit collagen synthesis, toxic chondrocytes, exogenous routes-inhaled, topical, oral, injectable, rectal)

what are some examples of drugs which use exogenous routes of steroids?

prednisone, triamcinolone, dexamethasone

what are the conditions/indications where we see cortisone injections?

bursitis, tenosynovitis (inflamed lining around tendon), osteoarthritis

what are some contradictions of cortisone injections

infection, prosthetic joint, fracture, achilles or patellar tendinopathies (most powerful tendons so more physical stress and injection around causes high risk for rupture)

what is the relative C/I for cortisone injections?

anticoagulant, IDDM (insulin dependent diabetes melitus), hemarthrosis, immunosuppression 

what are the possible ADRs of cortisone injections?

damage to cartilage/tendon, infection, post-injection flare 10%, skin atrophy, tendon rupture, bleeding

is there a specific form of cortisone injections that is more preferred?

no superiority of specific forms (hydrocortisone, methylprednisolone, triamcinolone)

what are the characteristics of opioids?

u-opoid receptor antagonists, oral IM, IV, epidural, intrathecal (in and around spinal cord), transdermal (fentanyl patch), intranasal

what are the medical uses of opioids?

pain relief (acute, chronic), sedation, anesthesia (spinal, epidural, intrathecal), cough, diarrhea, dyspnea

what is the main drug used in sports medicine?

codeine, the rest are banned

what are the side effects of opioids?

nausea, dizziness, constipation, sedation, confusion

what are some high risk factors of opioids and characteristics of overdose?

high risk of physical and psychological dependency (tolerance, withdrawal and addiction), overdose (respiratory depression, naloxone-narcan kits)

what are two main compounds of cannabinoids?

CBD (non-psychoactive) and tHC (psychoactive)

what are the methods of administration for cannabinoids?

oral nabilone (cesamet), nabiximol sprays, oils, inhaled 

how are cannabinoids absorbed?

oral = lower peak concentration, slow onset compared to inhalation

how are cannibanoids distributed?

extensively into fatty tissues, can be detected in blood up to 33 days after last use

how are cannabinoids eliminated and metabolized?

metabolized in liver, elimination through feces 

what are some indications/uses of cannabinoids?

chemotherapy-induced N/V, spasticity, neuropathic/cancer pain, seizures, wasting syndromes (HIV/AIDS, cancer), may have impact in PTSD, no supportive evidence for acute pain, headache, fibromyalgia, arthritis

what are the acute effects of cannabinoids?

sedation, dizziness, sensory disturbance, hallucination/paranoia, euphoria, dysphoria, anxiety, cognitive impairment, hyoptension, tachycardia, hyperemesis 

what are the chronic adverse effects of cannabinoids?

anxiety, depression, psychosis/schizophrenia, cognitive impairment, lung disease, carcinogenicity (smoked)

Is there any evidence of death secondary to cannabinoid overdose?

no

what is cortisone for?

pain, anti-inflammatory

what are opioids for?

limited use unless acute severe pain

What led to the creation of WADA?

1998 Tour de France, police seize prohibited substances from professional cycling teams, Willy vote caught with injection equipment, narcotics, EPO, growth hormones, testosterone and amphetamines

explain the timeline of the development of the WADA

1968 (IOC publish first banned list of drugs first summer olympics, testing still occurred just not as imprtoant), 1998 (tour de France doping scandal), 1999(IOC convenes world conference on doping in sport leading to creation of world anti-doping agency)

what finances WADA?

IOC finances half of WADA budgetary requirements

what is the importance of the WADA code?

adopted by many sports organizations including international federations, major event organizations, national Olympic committees, national Paralympic committees and national anti-doping organizations, head office in Montreal since 2002

what is the WADA code when was it made?

in 2004, core document that harmonize anti doping policies, rules and regulations within sport organizations and among public authorities around the world, latest revision in 2021, 8 standards and 12 guidelines 

what is the purpose of the 8 mandatory international standards for WADA?

harmonization of specific technical and operational parts of anti-doping programs, adherence to international standards is mandatory for compliance with code

what are the main areas in the 8 mandatory international standards for WADA?

code compliance by signatories, education, prohibited list, therapeutic use exemptions (TUE), testing and investigations, laboratories, results management, protection of privacy and personal information

what is the purpose of the 12 non-mandatory guidelines for WADA?

recommended practices for aspects of anti-doping, not mandatory but offer technical guidance to anti-doping organizations in the implementation of programs

what are the 12 guidelines in WADA?

guidelines for education, for result management, for therapeutic use exemptions, for privacy, sample collection, for gathering information and sharing intelligence, implementing an effective testing program, for sample collection personnel, laboratory guidelines (hGH biomarkers test, TUE enquiries by accredited laboratories, conducting and reporting subcontracted analysis and further analysis for doping control, gene doping detection based on polymerase chain reaction) 

what are the WADA activities?

code compliance monitoring, education, scientific research, publish annual list of prohibited substance and methods, manage lab accreditation, TUEs and athlete biological passport, coordinate anti doping activities through anti-doping administration and management system, global anti-doping development, athlete outreach, cooperation with law enforcement and anti-doping organizations

what is meant by anti-doping violations?

occurrence of one or more of the anti-doping rule violations set in article

what are some anti-doping violations?

presence of prohibited substance or its metabolites or markers in sample, use or attempted use by athlete of a prohibited substance or method, evading, refusing or failing to submit sample collection, 3 missed tests and/or filing failures in 12 months, tampering or attempt with doping control, possession of prohibited substance or method, trafficking or attempted in prohibited substance or method, administration or attempted administration in-competition of prohibited substance or method our out-of competition, complicity, prohibited association

what is meant by complicity in anti-doping violations?

assisting, encouraging, aiding, abetting, conspiring, covering up or any other type of intentional complicity involving an anti-doping rule violation