Pharmacology and Toxicology Study Guide PDF

Topic 1: principles of nutrition and health 1.​ Science of Nutrition 1.1 How is nutrition changing over time? Then, now and future. -​ identifying/ discovering nutrients and their role in deficiency diseases -​ Try to determine optimal levels for chronic disease prevention + performance -...

Topic 1: principles of nutrition and health 1.​ Science of Nutrition 1.1 How is nutrition changing over time? Then, now and future. -​ identifying/ discovering nutrients and their role in deficiency diseases -​ Try to determine optimal levels for chronic disease prevention + performance - scurvy; vitamin C -​ Future - further optimization - personalized, precision, individual, nutrition recommendations based on genetics, external environment (behaviour, socioeconomic, food security) -​ Multiple nutrients, exercise, sedentary behaviour, sleep, gut microbiome -​ Nutrition and _______ 1.2 What are other recognized factors that contribute to health? -​ Occupational - meaningful work -​ Spiritual - beliefs and values -​ Emotional - feelings and mental health -​ Social - family, community, environment -​ physical - exercise, sedentary behaviour and sleep -​ Many other factors for health 1.3 Know definition - What is the difference between Food vs. Nutrition? -​ Food → what we consume (processed, functional, organic, supplements) -​ Nutrition → study and science of food for nourishment. Includes health + disease risk. Food safety, security and global nutrition 1.4 What is the relationship between nutrition and disease? -​ Food is not medicine, food is nourishment -​ Too litlle/too much contributes to disease either directly (defiency i.e scurvy) or contribute to varying degrees ( excess energy, overweight, obesity) indirect -​ Problem magnified b/c nutritional needs vary by individual -​ Population recommendations vs individual treatment - i.e canada's food guide -​ Hazard vs risk; hazard is yes or no; risk - shades of grey - eating sausage proven to cause cancer, but risk is low -​ Smoking is hazardous and ( yes) cause lung cancer - risk is high 1.5 Definitions/classification of nutrients What are nutrients? -​ Proteins, carbs, fats, minerals, vitamins, and water Organic vs inorganic -​ Protein, carbs, fat, vitamins (carbon containing) -​ Inorganic - minerals and water Macro vs micro  -​ Macro - protein, carbs, fat -​ Micro - minerals and vitamins What is not a nutrient but provides energy + carbon containing -​ Alcohol 2.0 Nutritional assessment -​ Physical exam, health history, anthropometric (skinfold, body fat, and BMI, height and weight) and biochemical/clinical measures (blood tests) 2.1 Dietary tools -​ Dietary history, 24 hour recall, food frequency questionnaire, 3-7 day diet records -​ Dietary history - takes form of questionnaire -​ 24 hour recall - ate yesterday -​ food frequency questionnaire (FFQ) - list of foods frequency intake -​ Diet records - diary of food intake (best to include weekend and weekday) -​ Pros and cons - recall accuracy, recall bias (not truthful), giving preferential answers, quantitation - not known how to measure - poor perception -​ Pros - gains useful information 2.2 Definitions to know – undernutrition and overnutrition -​ Undernutrition - low energy or nutrients - nutrient deficiency - pellagra(niacin) rickets(vitamin D) scurvy(vitamn C) anemic(iron) 2.3 Definitions to know - Primary deficiency, secondary, subclinical -​ Primary - inadequate consumption -​ Secondary - deficiency due to absorption, excretion, utilization -​ Subclinical deficiency - deficiency in early stages with typically covert symptoms -​ Overt - obvious -​ Covert - not obvious -​ Primary deficiency - i.e. scurvy and vitamin C (ascorbic acid), collagen synthesis (fingernails, teeth, hair), general weakness, fatigue, aching limbs 3.0 Evaluating Science 3.1 Scientific Method -​ See fig 1.5 -​ Observation, hypothesis (scientific guess, direction and magnitude of effect), experimental design, collect/analyzes data, make interpretations and repeat 3.2 Experimental design -​ Sample size (adequate) - depends (n = 30) most studies could be thousands -​ Model system appropriate (animal/human), recognition of strengths and limitations, appropriate stats -​ Appropriate controls present - reference or normal/healthy group 3.3 Types of designs -​ See fig 1.6 -​ Human vs experimental (animal and cell culture) -​ Hierarchy of studies (clinical/drug) trials, aka, randomized control trials, perspective longitudinal, cross-sectional, case control, animal and cell culture Read Freudenheim paper. – review next class -​ what is an ecologic study? -​ population based, hypothesis generating, based on estimates at the population level i.e. per capita sales data -​ Weakness - not precise… over/underestimate outcome measures of interest -​ Not invasive, population based numbers, estimate Read Ho’s paper -​ what is major criticism of RCTs?– review next class -​ typical pharma RCT - 10’s if not hundreds of thousands of subjects, multiple years, multiple cities, multiple countries….. Cost are high, a lot of money.. Billions -​ How about food companies - kellogs, nestle…. They are probably about 1/100 or 1/100 capitalized, (i.e. Novo Nordisk, Denmark - makes insulin and ozempic) - worth more then the country itself -​ Impossible for food companys to mount RCT’s at the ame level as pharma -​ Impossible for nutrition studies to mount the same level of evidence as RCT’s. Advociating for new perspective on what constitutes high level of evidence for nutrition studies, pharma studies can test single molecules, nutrition studies are confounded by background diet, further confounded by nutrient to nutrient interactions 3.4 Evaluating media reports, ‘expert’ blogs -​ Check the literature, fact check, look for credentials (masters/PhD/MD/Nurse/Pharma/Kin, previous experience to field -​ Look at intention, motivation/sponsorships - look for potential conflict of interest (COI) -​ What about testimonials - think about COI, credentials… but most likely influence by those around you - immediate social circle (family,friends,barber,neighbour) 3.5 Credible sources/experts of nutrition -​ Credentials of the individual → bachelors, Msc, Dr., Dr. Naturopath, Homeopathy, Kin, Nurses, Pharmacists, dietitians -​ Still be skeptical tho -​ Dietitian of Canada (DC), Canadian Nutrition society (CNS), Health Canada, Non-government agencies (NGO’s) - Heart and stroke of Canada, Diabetes Canada, Canadian cancer society 3.6 How to evaluate the literature. Get the facts Read article by Boushey et al. – review next class. -​ what is alpha? -​ P-value - less than 0.05 - statistical test - significant difference; less than 5% chance that difference was random -​ what is key point being made about hypothesis statement? -​ is it well written, identification of independent and dependant variable, direction and magnitude of effect -​ Read this paper to be ‘critical thinker/evaluators’ - looking at both sides of the coin, being informed, not take things at face value - think is active vs passive -​ If you had to fact check a numerical value? Does it make sense; is it correct -​ When fact checking or reading primary literature (scientific paper) - dont be passive, but be active and critical - often times headlines are biased or only tell a part of the story -​ Who -​ What -​ When -​ Where -​ Why -​ How -​ Other questions -​ Context matters - specific to small groups/populations or generalizable to public -​ How much (dosage - feasible for intake): sample size (small/big) -​ Early vs late stage research (maturity) -​ Hypothesis or objective - did they answer the question; so what? What is the relevance/importance of the finding… maybe not obvious in natural sciences 3.7 Aspartame Exercise -​ Artificial - doesn't exist in nature (man-made) -​ Used instead of sugar/alternative with “low calories” substitute for sugar -​ Most studied sugar substitute -​ What is the concern about aspartame - leads to alzhemiers, liver cancer → is partly or not even true -​ What is the safe amount of consumption? EFSA - European food safety authority -​ Acceptable daily limit - 40 mg/kg body weight -​ Can of diet coke contains - 180 mg of aspartame -​ Average adult weighs 70kg (154lb) -​ 40 mg/kg x 70 = 2800 mg/day = 12.5 cans/day GMOs? -​ Genetically modified organism -​ Genetically modified fruits/vegetables i.e. papaya and corn  -​ Better yield, grow in different climates/regions, better tasting (browing apple -​ People dont like artificial/ man made and natural is preferable (not always better) -​ Modern GMO uses targeted genetic technologies to accelerate change/identification of desired traits which traditionally we call selective ‘breeding” Topic 2: DRI’s for class 1. Height Exercise · ​ Before we look at DRIs we need to do a little exercise to help you understand the concept of DRIs · ​ What do you notice about the simple distribution of heights in class from low to high -​ Linear and positive · ​ Where do the majority of values fall around? -​ Mean +/- SD · ​ What happens when distribution is grouped by increments of ie (5 or 10 cm)? -​ Normal distribution or bell curve · ​ Where is the average or mean? -​ Central value (where 50% of observation, are below or above the mean · Does this mean that everyone falls within the mean? -​ Roughly ⅔ (60%) or +/- 1 SD (68%) fall around the mean 2. Evolution of dietary requirements in Canada / USA · ​Recommended dietary allowances (RDAs), then became · ​Recommended nutrient intakes (RNI) and now · ​Dietary Reference Intakes (DRIs) – harmonized to both Canada and USA 3. DRIs – major goals -​ Are for healthy people -​ Preventing deficiency disease in healthy people -​ Reduce chronic disease in healthy people -​ Recommendations by ages, by gender, life stage (pregnancy/lactation) 4. DRIs values are nicely organized in Fig 1.4 -​ Represent a set of values - see fig 1.4 -​ DRI for most nutrients - not all nutrients have DRI values, for ex, phytochemicals and even some fatty acids -​ DRI for energy and macronutrients → set of 6 values - note later will introduce a 7th - 4 for individual nutrients and 2 for energy 5. Estimated average requirement – EAR · ​This is an intermediary calculation to determine RDA · ​For example, EAR for iron is 8.1 mg/day; 50% is always peak and at that peak, the average requirement is 8.1 mg/day -​ The EAR only tells us what half of the population requires i.e. for women 19-30 yrs iron requirement is 8.1 mg/day. The RDA for men is EAR + 2SD = (50+47.5) = 18 mglday for 97.5% or 97-98% of the population 6. Recommended Dietary Allowance – RDA -​ The average daily intake levels, estimated to meet the needs of nearly all people in a specific group 7. Adequate Intake – AI · ​When there is insufficient human evidence to establish RDA, an AI is used · ​AI = Estimated values observed in population ie vitamin K and fluoride -​ At some future date, AI’s may be updated to become RDA’s 8. Tolerable Upper limit – UL -​ Not all nutrients have UL -​ Highest level where risk of toxicity is low, important does not mean it is healthiest level -​ No benefit exceeding intakes beyond AI and RDA -​ UL’s established due to increasing use of supplements above AI and RDA -​ The gap between the RDA and UL (for nutrients with a UL) represents benefits/risk = 0 -​ UL’s established using modelling specific to each nutrient 9. Estimated energy requirement - EER · ​i.e. Adult male · ​EER = 662 – [9.53 x age] + PA x [(15.91 x weight) + (539.6 x height)] · ​Weight in kg, height in metre, PA = physical activity value -​ Based on age, gendern weight, height, and physical activity  10. Acceptable macronutrient distribution ranges (AMDR), Fig 1.4 · ​CHO – 45-65% · ​Fat – 20-35% · ​Protein 10-35% -​ For energy, providing nutrients we have AMDR, a range of intake expressing as % energy 11. Energy density of macronutrients: proteins and carbohydrates 4kcal/g; lipids 9kcal/g; alcohol 7kcal/g 12. Calculate energy from macronutrients. Energy is measured as calories or joules · ​kilocalorie (kcal) – energy required to raise temp 1kg (1L) of water by 1oC · ​1 kcal = 1 Calorie =1000 calories · ​In science Calorie is written with capital “C” = 1kcal, but in many publications, written (incorrectly) using lower “c” · ​Written as “Adults eat on average a diet of 2500 calories…” actually means 2.5kcal · ​Should be written as “Adults eat on average a diet of 2500 kcal or 2500 Calories (with big “C”). · ​or joules (IUPAC); 1 kcal = 1000 calories = 1 Calorie = 4.184kJ Lets work through example on page 13. Mother consumes 2500 kcal per day. 300g of carbohydrates, 90 g of lipids and 123 g of proteins Calculate %energy consumed from each macronutrient Use this formula to solve all = amount x energy density % energy = energy of macronutrient / total energy i.Carbohydates. ii.Fats iii.Protein Another problem. The uncle consumes 500 g of carbohydrate, 120 g of lipids and 150 g of protein. Calculate the % energy consumed from each macronutrient.  13. Nutrition and Drug Toxicology · ​See slides · ​ED, effective dose; LD50, lethal dose at which 50% of population dies · ​Follow graph along x-axis to interpret results/effect at a given concentration/dose/intake · ​Drugs usually have a linear shape, at low doses they are therapeutic, but at higher doses adverse events and death occur · ​If we look at nutrients, we see a U shaped curve; width at bottom of curve can be very narrow or vary widely. It’s the upside version of our RDA curve where we are looking at negative/adverse events, which are the least within the optimum range. 14. New DRI values based on chronic disease risk reduction (CDRR) https://www.nap.edu/catalog/24828/guiding-principles-for-developing-dietary-reference-i ntakes-based-on-chronic-disease -​ 7th DRI value, guiding principles published in 2017 -​ While DRI’s focused on prevention of deficiency of nutrients and overall chronic disease prevention, these new DRI values are based on best evidence where there is an established biomarker for specific conditions Rationale for new class of DRI values https://www.nap.edu/catalog/24828/guiding-principles-for-developing-dietary-reference-i ntakes-based-on-chronic-disease First CDRR values for sodium https://www.nationalacademies.org/news/2019/03/sodium-and-potassium-dietary-refere nce-intake-values-updated-in-new-report -​ First set of CDRR values established for sodium in 2019 related to cardiovascular disease, hypertension, systolic/diastolic BP; the evidence for potassium also reviewed, but insufficient evidence to establish CDRR  -​ Essentially is not a criteria Case for non-essential nutrient https://cdnsciencepub.com/doi/full/10.1139/apnm-2020-0994 -​ EPA and DHA - fish oil Topic 3 - nutrigenomics 1. What is ‘omics’ and what is nutrigenomics? -​ Use of modern advanced technologies to analyze large numbers of molecules -​ I.e. from one at a time to dozens to hundreds to thousands at a time -​ Genomics - genes -​ Transcriptomics - mRNA -​ Proteomic - proteins -​ Metabolomics - metabolites -​ Nutrigenomics - study of gene x diet interactions 2. Omics and personalized health/medicine -​ Omic technologies gives us the ability to know in great detail (almost comprehensively) many facets of our makeup/biology -​ Catalyst - human sequencing project - global vs corporate race -​ There are 30,000 human genes and only 0.1% difference between individuals (poker analogy → we have the same number of cards but different hands); 0.1% is considered small but consider 3 billion base pairs in the human genome -​ Genomics - we can sequence whole genomes very quickly 3. What is nutrigenomics? -​ Historically known discreetly as nutrigenomics AND nutrogentics: today we just use the umbrella term nutrigenomics -​ Think of a radio -​ Nutrigenomics - influence of food on genetic response - on/off -​ Nutrigenetics - influence on genetic variation (of some gene) on response to food-volume dial -​ Field of nutrigenomics gives uss ability to personalize nutrition recommendation based on our genes 4. What are types of genetic differences of relevance to nutrigenomics  -​ Most common study are single nucleotide polymorphisms (SNPs) difference in one base pair (AT or GC) -​ Other genetic differences - gene mutations deletion of portion of genes, gene arrangement, chromosomal arrangements, copy # variations (CNVs) 5. How does genetic variation influence response? Example: taste receptor for bitter -​ AA (high), AT (intermediate), TT (low) -​ Remember, 3 base pairs makes a codon which equals an amino acid -​ A simple difference in one base pairs may change the amino acid sequence of the protein -​ A different amino acid may -​ Alter the change of the protein - thus altering interaction with other proteins/ molecules -​ Shape of the protein - Altering interaction with other protein/molecules -​ Alter the catalytic site, regulatory elements 6. SNPs are modifiers of human response and context dependent · ​Coffee example. Read Cornelis paper · ​TNF and obesity paper. Read Fontaine-Bisson paper -​ Coffee - if you are a coffee drinker, the gene that metabolizes caffeine matters. If you are a fast metabolizer, you can drink 4 or more cups of coffee a day: if you are a slow metabolizer, no more than 1 cup. If genetics were not considered, everyone is at risk, but considering genetics gives us a different view -​ Think forest vs trees → TNF - genetic variation is unmasked in a disease state: system is stressed with disease (think engine problems at high speed: healthy state, snps did not matter 7. Limitation of SNP studies -​ SNP’s only look at genes, regulation of proteins and metabolites are not considered -​ SNPs are only one piece of the puzzle of complex (polygenic) dieseases. Recall that there are also other lifetsytle factors i.e. physical activity, pollution, emotional, etc. -​ Cost remains prohibitive. $500/chip -​ Ethics - protection of your genetic information  8. Omics – the promise -​ Detection and monitoring of disease -​ Monitoring of treatment -​ Personalized patient treatment -​ Aid in design of new drugs -​ AI will accelerate all of the above 9. Omics – challenges -​ Integration of omics -​ Timing of exposure/ snapshot -​ Data overload → may be overcome by AI -​ Context development, conditional/masking Topic 4 - healthy diet 1. A healthy diet -​ Adequate - enough energy - nutrients and fibre -​ Nutrient dose - aspire to nutrient-dense foods (high amount of nutrients with least amount of calories vs energy dense foods, just calories and no nutrients) -​ I.e avocado - nutrient dense -​ i.e. sugar-filled granola bar - energy dense -​ Moderate, not too much and not too little (portion control) -​ Balanced, combination of foods that provides proper portion of nutrients -​ Varied, eating variety of foods increases likelihood of obtaining nutrients the body needs 2. Food labels -​ ingredient list, is descending order by weight, helpful for identifying desirable or undesirable nutrients -​ Nutrition fats table, mandatory for most repackaging foods - acceptions fresh fruit, vegetables, raw meat, poultry, fish/seafood, alcohol, roadside farmers market -​ Nutrient content claims, statements regarding the amount of a given nutrient - government regulated -​ Diet health claims, statements regarding the health effects of a nutrient - government regulated 3. More about nutrition facts table -​ Serving size -​ Calories per serving -​ List of nutrients, 13 core nutrients - fats, saturated fats, trans fats, cholesterol, sodium, carbohydrates, fibres, sugars, protein, calcium and iron - Vitamin A and C removed, and potassium was added in 2019 -​ Present daily value: based 2000 kcal: tells us 2 things - is there is a little or there is a lot - 5% is low and 15% is high: aids in comparing between products -​ There is no daily value for cholesterol -​ There is no daily value for sugar -​ There is no daily value for protein - generally believed that everyone is consuming enough protein: everyone has different protein needs 4. Health claims · ​Function claim – “claims about the specific beneficial effects that the consumption of a food or a constituent of a food” ie Consumption of green tea helps to protect blood lipids from oxidation; ¼ cup of product X contains 7 grams of coarse wheat brain, which promotes regularity” · ​Nutrient function claim “are a subset of function claims that describe the well-established roles of energy or known nutrients that are essential for the maintenance of good health or for normal growth and development” Vitamin A aids in the development and maintenance of night vision” – full list on CFIA website → canadian food inspection agency · ​US Health claims – far more claims permitted, regulatory approval process is different (whether its better/worse is debatable). Function claims called structure-function claims are permitted without FDA approval. Ie nutrient x “improves memory”. → US regulations are more permissible while canada regulations are more conservative 5. Front of Packaging -​ Helps consumers better understand the quality of the product -​ Guiding stars → Loblaws -​ Health check → heart and stroke of canada -​ Approved in 2020 → magnifying glass - by health Canada - focused on 3 nutrient of concern sugar, sodium, and saturated fat; all companies need to comply by 2025 -​ Europe has its own system similar to Canada 6. Canada’s Food Guide -​ Not a food pyramid or food plate, USA -​ Last updated in 2019; last version was in 2007 (12 years) -​ Philosophy is ongoing/continual updating via website -​ Gone is the iconic rainbow - size of rainbow are meant to emphazie relative population - 4 food groups - vegetables and fruit, grain products, milk and alternatives, mand and alternatives (beans, lentil, and tofu) -​ Key message of new 2019 → significant anf major overhaul, not a simple update -​ 3 food groups, proteins got merged together -​ Emphasizing proportions and overall diet quality vs individual nutrient intake - more readily understood by consumers - simpler messaging -​ Use food labels, limit foods high in sodium, sugars, and saturated fats → be aware of food marketing especially for children - alcohol limit or do not consumer - also provides guidance for physical activity i.e. 150 min/week of moderate/ vigorous activity for adults (18-64 yrs) -​ Specific messaging, eat a variety of healthy foods each day, have plenty of vegetables and fruit, choose whole grains, eat protein foods (more plant bases), make water your beverage of choice -​ Also messaging around, be mindful of eating habits, cook more and eat less processed food, enjoy food , eat more with others (social benefits) 7. Eating out – Menu labelling -​ Problem is - high calorie, high fats, high sodium, large portion size -​ Need to educate consumers about what is on the menu - calorie labelling: startd in NY now more common -​ The hope is to moderate calorie intake -​ Sugar or “sin” tax - mexico implements sugar tax for soda consumption - promising; Denmark introduces fat tax in 2012 - repeated -​ Taxes are not the only answer 8. Why do we eat? -​ We have physical (pressure/bulb) and chemical/hormonal signals -​ Amount and type of food (satiety value, protein is more filling then>fat>carbs); bulk - solids > liquids -​ stomach/intestinal cells can signal pressure/fullness -​ Blood glucose -​ Hormones acting at hypothalamus -​ Neuropeptide Y - brian neurotransmitter, promotes food intake -​ Leptin - adipose, promotes feeling of satiety -​ Cholceystolsin - intestinal, decreases appetite  -​ Serotonin - brain neurotransmitter, derived from tryptophan, promotes satiety -​ Ghrelin - signals for hunger 9. Why do we eat? -​ Maintaining blood sugar is physiological requirement for life -​ Regulated by pancreatic hormones - insulin and glucagon -​ Sugar cane come from carbohydrates and protein, but not fat 10. Other reasons for why we eat -​ Sensory, food stimulates sense of sight, smell taste, texture sound i.e. buying popcorn at the movies -​ social/culture: christmas, thanksgiving, nibbling while studying, emotional stress conflict -​ Learned factors: family occasions, community, religion 11. GI disturbances. Food intolerance: -​ Is a cluster of GI symptoms (gas,pain,diarrhea) that occur following consumption of a particular food Food allergy: -​ Is a hypersensitivity reaction of the immune system to a particular, component - usually a protein - in a food Celiac disease (or Celiac Sprue): -​ Characterized by damage to lining of the small intestine - poor nutrition absorption/malabsorption -​ Caused by immune response to gluten protein, found in wheat, rye and barley -​ Gluten attention in 2013/2014 -​ Many gluten free foods lack micronutrients -​ Only 1% of population is truly affected by celiac - need intestinal biopsy -​ Ongoing research is trying to understand “gluten sensitivity” Crohn’s disease: -​ Can affect any part of GI, inflammation can occur anywhere along th eGI leading to thickening of the intestinal wall -​ Speculated to be viral/bacterial immune reaction -​ Symptoms include diarrhea, abdominal pain, rectal bleeding, weight loss, fever, anemia -​ Treatment - surgical, anti-inflammatory drugs, nutritional supplements to correct deficiencies Ulcerative Colitis: -​ Similar to chrons but only occurs in the colon; recall all food is digested, absorbed in small intestine -​ Not an immune response to food but to a virus or bacteria -​ Patients may avoid foods that cause GI discomfort -​ Treatments include - anti-inflammatory drugs, more severe requires surgery