Parm Exam 1 (3-4) Flashcards
e.g. rs10516526
SNPs: Single nucleotide polymorphism
e.g. rs10516526 G
Alleles: Different DNA sequences at a locus
e.g. rs10516526 GG, GA, or AA
Genotypes: Pair of alleles at a particular locus
A set of DNA variations, or polymorphisms, that tend to be inherited together.
Haplotype:
Factors Affecting Drug Response
1 Environment:
Diet
Lifestyle
Socioeconomics
Others.
2 Biology:
Age
Sex
Others
3 Genetics*
the study of how genes affect a person’s response to drugs
Pharmacogenomics
Systemic Approach to Genetic Variations
Identify the Genetic variations and what can be affected:
Enzyme, transporter, receptor, disease.
Silent: no functional effect.
Determine who is impacted:
Individuals or population.
Identify how it is relevant to drug:
Affect drug PK or drug PD.
Resulted in drug efficacy, toxicity or drug dosing
Has no effect.
Determine how Relevant to a disease:
Increase or decrease drug susceptibility or condition.
Utility as a screening or diagnostic tool.
Phase I
mods:
Hydroxylation
Hydrolysis
Oxidation
Reduction
HHOR (whore)
ex: P450 CYPs
Phase II
mods: Conjugation
Ex:
UGT: Glucuronidation
NAT: Acetylation
GST: Glutathione conjugation
SULT: Sulphation
MT: Methylation
GAGS M(e)
Genetic variations and Enzymatic activity (Phenotypes):
Extensive metabolizers (EM or WT):
Individuals who are homozygous for the two alleles coding for “normal” enzyme function.
Poor metabolizer (PM):
Individuals who are homozygous with two variant alleles resulting in inactive or absent enzymes.
Intermediate metabolizer (IM):
Those who are heterozygous manifest phenotype with reduced function of heterozygous EM.
Ultra-rapid metabolizer (UM):
Resulted from gene duplication or multiplication.
PGx of transporter MDR1
Reduced gene Expression -> Higher drug plasma level ex: Digoxin -> C1236T, C3435T, G2677T/A
Breast Cancer Alternative treatments
Aromatase Inhibitors:
Blocks aromatase enzyme:
Convert androgen into estrogen.
Anastrazole
Letrozole
Warfarin/Coumadin GG 1/1 and 1/2 dose
5-7mg
Warfarin/Coumadin GG 2/3 dose
3-4mg
Warfarin/Coumadin GG 3/3 dose
0.5-2mg
Irinotecan
UGT1A1*28
Neutropenia
Codeine (prodrug)
CYP2D6
PM: No analgesic effect
UM: respiratory depression
Clopidogrel (prodrug)
CYP2C19
PM: No drug activity
Common examples of “Narrow Therapeutic Window” Drugs:
warfarin
levothyroxine
digoxin
cyclosporine
tacrolimus
theophylline
carbamazepine
phenytoin
Bioavailability
Area Under the Curve (AUC) is used to measure bioavailability
AUC represents the total systemic exposure to a drug
Since IV drugs have 100% bioavailability, their AUC is the reference
Things that reduce bioavailability:
Incomplete amount of Absorption
The First-Pass Effect (enteral drugs only – really just oral/NGT/PEG tube)
Absorption: In general, drugs that are good at diffusing through lipid bilayers are:
Small molecules
Lipophilic
Uncharged
1-Continuous capillaries
2-Fenestrated capillaries
3-Sinusoidal capillaries
1:CNS (Blood-Brain Barrier)
Skin
2:Lungs
Kidneys
Small intestine
3:Liver
Lymph nodes
p-glycoprotein (p-gp)
Efflux transporters are active transport proteins that move drugs out of cells.
It keeps many drugs in the intestine
It keeps many drugs out of the brain
ex: Allegra not Benadryl because it makes you drowsy (in brain)
Tablets/Capsules getting absorbed through the gut wall have additional considerations:
1-Dissolution of the drug from tablet or capsule form
Drug must be in solution to be absorbed
Different formulations dissolve at different rates (eg, SR, XL…)
2-Stability of drug
Against acid hydrolysis, digestive enzymes, other
3-Rate of gastric emptying
Absorption is much faster in the small intestine
More surface area, permeability, blood flow
The speed of getting to the small intestine limits the speed of getting absorbed
Food slows gastric emptying
4-Intestinal motility and drug interactions
pH, surface area, permeability, and efflux-transporter density varies along intestine
Drugs may bind to contents of intestine, preventing absorption
Drugs given by IM/SQ/ID injection have 2 possible pathways to the systemic circulation:
1- Diffusion through capillary membranes
Very forgiving of polarity and charge; less forgiving of size
2- Getting carried through the lymph system
The body’s ‘garbage collector’
Large molecules, proteins go this route
Lymph system moves very slowly — makes absorption slow
Enzymatic breakdown of drugs can occur in lymph nodes
Speed of absorption also affected by site of injection, local bloodflow and temperature, rubbing at the injection site
Not getting absorbed by the gut wall (excretion into feces)
Breakdown (metabolism) by the gut wall
Excretion into bile by liver
hazards along the way for enteric drugs
A key difference between parenteral and enteral drugs
Enteral drugs go through the liver before they reach the systemic circulation, as well
Which has better bioavailability:
Drug X Parenternal dose:10mg, oral dose:30mg
Drug Y Parenternal dose:1mg, oral dose:10mg
Drug X because you need to 3x it to get to F(bioavailability). compared to needing to 10x drug Y
Where the drug distributes to in the body depends:
How well it diffuses through different membranes (size, lipophilicity, charge)
What it likes to bind to (proteins in the plasma or other tissues)
Some drugs bind heavily to plasma proteins (“protein-bound” drugs) and cannot diffuse
Only “unbound” or “free” drug can leave the bloodstream (or be active)
Some drugs have a particular affinity for certain tissues
eg, bisphosphonates (osteoporosis drugs) have a high affinity for bone minerals
tetracyclines, too —> teeth staining
A drug’s Volume of Distribution (Vd) gives you an idea of how the drug gets distributed (whether it stays mostly in the bloodstream or enters other tissues).
If it is doesn’t leave bloodstream vs Going everywhere?
If the drug stays in the bloodstream, then the Volume of Distribution will be close to the volume of the blood (eg, warfarin Vd= 8 L)
If the drug distributes widely around the body, the Vd will be large (eg, chloroquine ~15,000 L)
The major enzymes involved in metabolizing drugs belong to the ______ family.
Cytochrome P450 (CYP450)
A few important CYP450 family members:
WARFARIN, NSAIDS, codeine, metoprolol, oxycodone, risperidone, tramadol, caffeine, cyclobenzaprine, propranolol, amitriptyline, citalopram, diazepam, omeprazole, alprazolam, atorvastatin, carbamazepine, erythromycin
What will happen if you take St. John’s Wort (INDUCER of metabolizing enzyme of Simvastatin) and Simvastatin together
Plasma levels of simvastatin will be lower than expected.
Elimination 2 routes
Metabolism is one way to eliminate a drug
Even though the drug is still in the body after metabolism, it is not in its original form
“Hepatic clearance” describes the rate of metabolism
Excretion is the other
Drugs can be excreted in breastmilk, breath, sweat, bile, urine…
Most excretion is renal
“Renal clearance” describes the rate of renal excretion
Clinically, when we talk about clearance, we are talking about renal clearance
In a healthy patient, the GFR is
120 ml/min and GFR is a proxy for the renal clearance rate, aka kidney function
Altered ADME in Elderly Patients: Absorption
-Decreased gastric acid secretion Impaired absorption of some drugs
- eg, iron, levothyroxine, some HIV drugs
- Decreased liver function Decreased first-pass metabolism
Increased levels of some drugs (eg, labetalol, propranolol)
Decreased levels of pro-drugs (eg, clopidogrel)
Altered ADME in Elderly Patients: Distribution
Distribution
- Decreased total body water Lower doses of hydrophilic drugs needed- eg, digoxin, ethanol
- Increased body fat Higher Vds of lipophilic drugs- eg, diazepam
- Decreased serum albumin Higher sensitivity to highly protein-bound drugs - eg, warfarin, phenytoin
Altered ADME in Elderly Patients: Metabolism
Metabolism
- Decreased liver function Increased levels of drugs with high hepatic CL
- eg, propranolol, morphine, some antibiotics
Altered ADME in Elderly Patients: Excretion
Excretion
- Decreased renal function Increased levels of renally cleared drugs
- eg, digoxin, lithium, NSAIDS, diuretics, some antibiotics
Altered ADME after Bypass
Accelerated gastric emptying
Delayed gastric emptying
Reduced first pass metabolism
increased need of supplements Iron and vitamins
Steady state concentration (Css)
When rate of drug in = rate of drug out.
One dose is eliminated per dosing interval.
The drug level in the body stays in a certain range
reached after 3-5 half-lives (t1/2s) of chronic dosing
how long it will take to get to the steady state concentration (Css) with chronic dosing with a drug that has a 3 hour half life (new dose every 3 hours)
9 -15 hours
Patient X is put on a heparin drip at a rate of 12 units/kg/hr.
Patient Y is put on a heparin drip at a rate of 18 units/kg hr.
Who will get to steady state faster?
They will get there at the same time (3-5 t1/2s)
t1/2 of heparin ~1.5 hrs, so in ~4.5-7.5 hrs
…but pt Y’s Css will be higher
Advantage of shorter dosing intervals relative to t1/2 :
Less fluctuation
Less effect of missed doses
