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Describe the role of pharmacogenomics testing in the treatment of patients.
Polymorphisms affect how well patients metabolize drugs. Poor metabolizers (PMs) need smaller doses of drugs (medication persists longer) and larger doses of prodrugs (metabolized into an active drug). Ultra Metabolizers (UMs) need larger doses of drugs and smaller doses of prodrugs, and so on.
What are the different categories of metabolizers?
Poor (PM) < Intermediate (IM) < Effective/rapid (EM) < Ultra (UM)
Describe the methods for testing clinical relevance of a drug for an individual.
- Cost-utility assessments use the QALY (Quality-adjusted life year) for the outcome.
- Cost-effectiveness assessments use the QALY or a variety of outcomes, including clinical events.
What are the Key junctions of metabolism?
- Glucose-6-phosphate -> glucose, pyruvate, or ribose-5-phosphate
- Pyruvate -> glucose-6-phosphate, oxaloacetate, lactate, alanine
- Acetyl-CoA -> CO2, fatty acids, 3-hydroxy-3methyl glutaryl CoA (-> cholesterol, ketone bodies)
What are catecholamines?
- Catecholamines (stimulated by the sympathetic nervous system) cause glycolysis, glycogenolysis, and triglyceride utilization to increase while causing glycogen synthesis to decrease.
- Ie, fight or flight, causing an acute (quick) reaction.
- These include epinephrine, norepinephrine, and dopamine.
What are glucocorticoids?
- These cause increased gluconeogenesis and glycogen synthesis, preparing the body for an acute catecholamine response.
- Glucocorticoids regulate gene expression, so the response takes hours or days.
Describe the two major pathways for alcohol metabolism and list the characteristics of these pathways
- Liver: Alcohol Dehydrogenase system (ADH): Ethanol -> acetaldehyde -> acetate
- Microsomal ethanol oxidizing system (MEOS): MEOS is an inducible system that requires NADPH since it generates ROS (reactive oxygen species)
What are the risk factors associated with type 2 diabetes?
- Waist circumference: Men: > 40 inches/102 cm, Women: > 35 in/88cm
- Triglycerides: > 150 mg/dl
- HDL-C: Men < 40 mg/dl, Women: < 50 mg/dl
- Blood pressure: > 135/85 mmHg
- Fasting glucose: > 100 mg/dl
Summarize the DPP (Diabetes Prevention Program) study
- The study asked if metformin or lifestyle intervention prevent or delay diabetes onset.
- Results: Metformin patients had a 31% reduction in risk, lifestyle change patients had a 58% reduction in risk.
- Small weight loss -> large decrease in risk.
- 1 kg weight loss -> 16% reduction in incident.
- These patients should still be screened for retinopathy
Summarize the look ahead trial study
- Look ahead asked "will intentional weight loss reduce the incidence of fatal and nonfatal cardiovascular and cerebrovascular events?"
- Patients who already had type II diabetes and exercised, reduced their diet, took in less than 7% of their calories as saturated fat, had fewer complications.
Describe the life cycle nutrition recommend for adults (ages 20-65).
- 2100-2800 Cal for men, and 1500-1800 Cal for women
- Fats: about 30% of total Cal, < 10% as saturated fats
- Cholesterol: <300 mg/day
- Fiber: 25-35 g/d
- Folate: 400 mcg/day
- Vitamin E: 15 mg TE/d
- Also, calcium, vit D, magnesium, Fe
What are the estimated energy requirements for adults and infants?
- Adults: 20-30 kcal/kg for women, 25-35 kcal/kg for men
- Infants: 90-110 kcal/kg
What are the nutrients of focus for adolescence?
Calcium, iron, vitamin D
What are the nutrients of focus for the elderly?
A, D, Fe, Ca, fiber, poly-fats
How much of an infants calories should come from fat and protein?
What are the supplemental nutrients of interest for a 6 month old?
Fe, Vit D, Fl, B12
How much of a toddler's calories should come from fat and protein?
- Fat: 30%-40%
- Protein: 5%-20%
What are the nutrients of concern for a toddler?
Iron, zinc, calcium
How does breast feeding affect a mother's diet?
- Breast feeding mothers will require an additional 750 kcal/day. Up to 450 of the calories can come from body fat.
- Nutrients of focus: lipids, slightly increased protein, DHA, cholesterol
How much of a children's or adult's calories should com from fat and protein?
- Fat: 25%-35%
- Protein: 10%-30%
What are the nutrients of concern for children?
Calcium, iron, vitamin D, zinc
What determines whether drugs are effective or harmful?
- Drugs need to be in the body long enough and in high enough concentrations to be effective (above the MEC (Minimum Effective Concentration) for the desired response and beneath the the MEC for adverse response).
- This is called the Therapeutic Window.
What are some of the factors affecting plasma drug concentration?
- Drugs requiring facilitated diffusion or active transport will have their concentrations limited by the number of transport proteins available.
- The uncharged weak acid or weak base versions of drugs can often pass through membranes. Remember, pH = pKa + log [A/AH]
- Only a portion of oral drugs are actually absorbed due to acidity, microorganisms, P450 enzymes in the GI tract, and the fact that these drugs first pass through the liver.
What is bioavailability?
- A measurement of how available a drug is to the body.
- Bioavailability = area under injected drug plasma concentrations / area under oral drug plasma concentrations for a given graph of a drug.
- The injected curve starts high and then lowers (like a slope). The oral drug start low, climbs a little, and the lowers (like a hump)
What is volume of distribution?
- Vd = amount of drug in body / drug concentration in plasma (or blood).
- This helps us understand binding since a drug that binds to many cells or proteins will have a low blood concentration and hence a high Vd.
- A low Vd means the drug stays in the blood.
Name two common inhibitors of P450 enzymes.
- erythromycin (and other antibiotics)
- grapefruit juice
Define Induction of Microsomal Enzymes.
When repeated drugs cause an increase in metabolizing enzymes, changing the body’s metabolism rates.
What stimulates glucagon release?
High protein meals and cortisol. Glucagon is also released at a basal rate,
What does epinephrine do?
It mobilizes fuel during acute stress (glycogenolysis, fatty acid release)
What does cortisol do?
It provides for changing requirements over time (amino acid metabolism, gluconeogenesis, fatty acid release from adipose tissue).
What can we learn from c peptide levels?
How much insulin is being produced vs how much is injected since the C-peptide is cleaved from proinsulin, but is not present in insulin injections.
Compare and contrast the first order and zero order drug reactions.
- v = Vmax[c]/(Km + [c])
- When [c] << Km, v -> v = Vmax[c]/Km. This is called first order kinetics.
- When [c] >> Km, v -> v = Vmax[c]/[c] = Vmax, so v = Vmax. This is called zero order kinetics.
- Most drugs follow first order kinetics
How do first and zero order elimination rates compare?
- first order kinetics: the elimination rate is proportional to the concentration of drugs: -dc/dt = kc, and c = c0e-kt.
- Zero order kinetics: the elimination rate is constant: -dc/dt = k, c = c0 - kt.
Compare the half life of first and zero order drugs.
- First order kinetics: t1/2 = ln 2 / k or 0.693 / k Half life is independent of concentration
- Zero order kinetics: t1/2 = ½ c0 / k. Half life is dependent on the initial concentration.
- k is a constant
- Clearance (CL) predicts the rate of drug elimination and is expressed as volume of plasma cleared from drug per hour (Liters/hour).
- t1/2 = 0.693 Vd / CL (Vd = volume of distribution)
How does half life affect the concentration of a regularly administered drug?
- Increased concentration results in increased elimination, so an IV drip will reach a steady state after about 5 half lives of elimination.
- The steady state concentration (Css) is directly proportional to R0 (the constant infusion rate).
- Css is inversely proportional to the clearance, CL. Anything that changes clearance will have an inverse effect on Css.
Describe the different fuel sources used by the body for gluconeogenesis.
- Lactate, amino acids, and glycerol can be used as substrates for gluconeogenesis. Acetyl-CoA cannot.
- The energy (ATP) for gluconeogenesis comes from fatty acid oxidation.
- Acetyl-CoA is broken down into acetoacetate and ß-hydroxybutyrate.
Identify the mechanism of diabetic ketoacidosis
- Decreased insulin ->
- increased hormone sensitive lipase ->
- increased fatty acid breakdown and ketone formation ->
- life threatening ketoacidosis (hyperglycemia + acidosis)
Describe the time frame for different energy sources
- Gluconeogenesis begins after 4 hours and becomes the major source of energy after 16 hours.
- After 30 hours of fasting, glycogen stores are depleted.
- The brain can use ketones as fuel after 3-5 days.
- Blood sugar can be maintained for 50-60 days. Death results from muscle wasting and complications rather than hypoglycemia.
To what extent to multiple SNPs predict diabetes risk?
the cummulative risk from a collection of SNPs is hard to define. Having 20 risk alleles may not make a difference from having 14 risk alleles.
What percentage of each type of diabetes typically occurs?
- Type I: beta cells destroyed. Accounts for less than 10% of cases
- Type II: Insulin resistance and decreased insulin production. Accounts for more than 90% of cases.
- Gestational: Insulin resistance caused by pregnancy. Occurs in 3%-5% of pregnancies.
What are the typical blood values for diabetes / prediabetes / normal?
- Method Normal Prediabetes Diabetes
- Fasting BG <100 mg/dl 100-125 mg/dl >126 mg/dl
- 2 hr OGTT (75 gm) <140 mg/dl 140-199 mg/dl >200 mg/dl
- Random BG - - BG >= 200 mg/dl
- HbA1c <5.7% 5.7%-6.5% >6.5%
What are the treatment goals for diabetes patients to reduce complications?
- Diabetes ABCs:
- Hemoglobin A1c < 7%
- Blood pressure < 130/80 mmHg
- LDL Cholesterol < 100 mg/dl
What are the long term complications of diabetes
- Macrovascular complications: Myocardial Infarction, heart failure, stroke, cognitive impairment, ulcers, amputations, aneurysms
- Microvascular complications:
- Retinopathy: cataract, glaucoma -> blindness
- Nephropathy: microalbuminuria, gross albuminuria -> kidney failure
- Neuropathy: peripheral, autonomic -> amputation.
What are some of the risk factors for type II diabetes?
- History of Polycystic ovary syndrome
- Gestational Diabetes Mellitus
- A child born over 9 lb or underweight
- Central obesity
- Acanthosis Nigrican
What is the most common form of MODY?
MODY3, affecting the hepatic nuclear factor 1 alpha protein (gene TCF1).
What is the second most common form of MODY?
MODY2, affecting glucokinase on the GCK** gene
What is the role of Human Leukocyte Antigen (HLA) in diabetes?
- There are many versions of the HLA-DR allele. Some increase risk and some can be protective.
- 95% of type I diabetics have DR3 or DR4 alleles, 30% have both. However, 50% of the population has DR3 or DR4.
- DR3: Antibody against pancreatic beta cells, causing late onset diabetes
- DR4: Antibody against insulin, causing early onset diabetes
What are some of the epigenetic risks for diabetes?
- Small birth weight babies are at an increased risk.
- If your grandfather was born during a feast time, your risk of heart disease and diabetes goes up.
- If your grandfather was born during a famine, your risk of heart disease and diabetes goes down.