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?
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?
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?
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)
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).