Pharmacokinetics: Part II Flashcards
drug administration =
oral
IV
intraperitoneal
subcutaneous
intramuscular
inhalation
absorption and distribution =
membranes of oral cavity, GI tract, peritoneum, skin, muscles, lungs
binding =
target site = neuron receptor
inactive storage depots = bone and fat
inactivation =
liver
excretion =
intestines, kidneys, lungs, sweat glands
excretion products
> feces
> urine
> water vapor
> sweat
> saliva
All drugs must be eliminated:
terminate effect
prevent excessive accumulation of drug = maintain proper levels
Mechanisms of elimination:
Biotransformation = metabolism
Active Form & Metabolites = excretion
Alternative to elimination =
accumulation of drugs or metabolite = adverse event and/or tissue damage
Comprehensive Metabolic Panel =
> blood test
measures:
> glucose level
> electrolyte and fluid balance
> kidney function
> liver function
Drug Metabolism
Chemical changes in drug following administration
Drug (active) -> metabolite (inactive/reduce activity)
Exception: Prodrug = Inactive when administered, metabolisms converts to active form
ex)
L-Dopa = dopamine metabolite, Parkinson’s Disease
Cortisone = corticosteroid metabolite, injection for inflammation
Metabolism: Drug to Metabolite
phase I: oxidation, reuction, and/or hydrolysis
> following phase I the drug may be activate or most often, inactivated
phase II: conjugation
> some drugs enter phase II metabolism -> conjugated products = usually inactive
End-product of metabolism:
More polar compound (covalent bonds)/ionized compound (ionic bonds): +/- charge
Non-lipid soluble or Water soluble
More easily excreted in urine
Oxidation:
Loss of electron or gain in oxidation state
Reduction:
Gain of electron or loss in oxidation state
Hydrolysis:
Original compound broken into separate parts due to uptake of H and OH
Conjugation:
Following oxidation, reduction, or hydrolysis = original drug coupled with endogenous substance
Yields a large polar/ionized metabolite by:
adding endogenous hydrophilic groups to form non-lipid/water-soluble inactive compounds that can be excreted by the body
Non-ionized form to Ionized form
Compounds transformed to non-lipid/more water-soluble form
NO LONGER PASS READILY THRU CELL MEMBRANES = EXCRETION
Water soluble drugs =
ionized
polar
charged
difficult to permeate cell membranes
ex) water soluble vitamins
Lipid soluble drugs =
unionized
non-polar
uncharged
easy to permeate cell membranes
ex) anesthesia
Phase I liver detoxification =
fat-soluble toxins
oxidation
reduction
hydrolysis
hydration
dehalogenation
nutrients needed:
vitamin B12, folic acid, glutathione
Phase II liver detoxification =
water-soluble toxins eliminated via: urine, bile, stool
conjugation pathways
sulfation
glucoronidation
acetylation
amino acid conjugation
methylation
nutrients needed:
methionine, vitamin B12, vitamin C, glutamine, folic acid
Elimination = ___ + ___
metabolism
excretion
Metabolism: Enzymes
Primarily produced in the Liver
Also produced in lungs, kidneys, GI epithelium, skin
Enzyme Induction:
enzyme production triggered due to the presence of a substance/drug
prolonged use of drugs = body adjusts and enzymatically destroys drugs more rapidly = enzyme induced drug tolerance = increased drug dosage
Enzyme Induction results in Drug Tolerance =
reduction in drug’s effectiveness
Drug Excretion
Primary site: Renal Excretion
Nephron = functional unit of kidney
Polar compounds/water soluble molecules/ionized compounds = excreted in urine
Metabolites filtered in glomerulus =
PCT -> LH -> DCT -> CD -> urine
1) proximal tubule
2) descending loop of Henle
3) thick segment of ascending limb
4) distal tubule
5) collecting duct
Other areas of drug excretion:
Lungs: excrete volatile drugs administered by inhalation = anesthetic gases
GI & liver: bile -> bile duct -> duodenum -> feces
Other minor routes: sweat, saliva, breast milk, tears, hair
Drug Elimination
Drug Metabolism (inactive metabolites) & Drug Excretion (intact medication)
Removal of a drug from the body
mostly through urination
kidneys clear metabolic waste and foreign substances by filtering the blood
Drug delivery > Elimination =
drug accumulation
Elimination > Drug delivery =
no therapeutic effect
2 Factors that effect the balance of drug accumulation, therapeutic effect & elimination:
Clearance and Half-life
Clearance =
volume of plasma cleared of a drug per unit of time
predicts the rate of elimination
volume/time
Half-Life =
amount of time it takes for the plasma concentration to drop by 50%
determined by drug chemical structure
Relationship of Clearance (CL) and Half-life
Increased clearance rate associated with decrease in drug half-life
Decreased clearance rate associated with increase in drug half-life
Clearance influenced by:
age, co-morbidities, blood flow, and drug concentration
Clearance at age 80 is estimated to be x2 age 30
CL= Q x [(Ci -Co)÷Ci]
Q= blood flow to the organ/tissue
Ci =entering drug concentration
Co =exiting drug concentration
Volume of plasma from which a substance is completely removed per unit time
Standard Unit: Rate: ml/min
A pt is advised to take Aspirin (primarily metabolized in liver). The blood which enters the liver has 200 µg/mL of aspirin and blood that leaves liver contains 134 µg/mL of aspirin. Calculate the hepatic CL of Asprin, when normal hepatic blood flow is 1500 mL/min?
495ml/min
if it takes 4 hours for a drugs concentration to fall from 50 units to 25 units its half life is =
4 hours
Dosing Schedules & Plasma Concentration
zero-order controlled release
sustained release
conventional release
controlled release =
release of medication (primarily diffusion) in correlation with drug concentration
Sustained Release =
release of medication over time
Conventional Release =
immediate release of drug
Factors responsible for individual drug response:
Genetics = Pharmacogenomics
Co-morbidities
Age
Drug interactions
Diet
Gender
Co-morbidities:
Concurrent diseases affecting the patient can modify drug response
Diseases of the organs of elimination =
liver and kidneys
Liver Disease:
Drugs that are largely metabolized in the liver are affected by liver diseases such as cirrhosis
Kidney Disease:
In patients with a compromised renal function, urinary excretion of drugs is diminished = clearance of many drugs reduced
Circulatory disorders:
Diminished vascular perfusion of one or more parts of the body is encountered in conditions such as cardiac failure
Drug-Drug Interactions
Majority = insignificant adverse effects
Synergistic: beneficial effects
cumulative effect drugs for HIV, cancer
Synergistic: adverse effects
barbiturates (anti-anxiety, sedative effect) + alcohol
Antagonistic:
reducing beneficial effects
phenobarbital (anti-seizure) + warfarin (anti-coagulant)
Serious adverse effects:
if one drug delays metabolism of another = drug accumulation = toxic
16.5% of population is 65+ = consume ___ of prescribed drugs in US
34%
64-69 yo = average __ medications
15
80-84 yo = average __ medications
18
Older Adults:
More sensitive to drugs and exhibit variability in response
Altered pharmacokinetics
Multiple and severe illness
Poor drug compliance
Antihypertensive drugs = orthostatic hypotension
> Beta blockers, diuretics, angiotensin converting enzyme inhibitors (ACE inhibitors)
A study of over 3,000 older adults examined drug-drug and drug-disease interactions
drug interactions are common among community-dwelling older adults and are related to the number of medications and hospitalizations
Main outcomes: potential drug-drug and drug-disease interactions according to established criteria applied to self-reported prescription and non-prescription drug use
Each additional prescribed drug raised the likelihood of having >1 type of drug interaction by 35-40%
Children:
Pharmacokinetic & pharmacodynamics data rarely available = relatively little clinical research
Liver & kidney immaturity = deficient in specific drug metabolizing enzymes
Paradoxical effect = opposite of expected effect
> Hyperactivity after administration of sedation drugs
Prolonged administration of corticosteroids = potential effects on growth, bone mass, & adrenal
Drug metabolism and pharmacokinetics change rapidly in first few months of life
Diet:
Foods, and the nutrients they contain, can interact with medications we take
This can cause unwanted effects
Most are not serious
Avoid ___ while taking antidepressants
red wine, beer on tap, aged cheese and cured meats
> Foods that contain tyramine can slow the metabolism of antidepressants and lead to severely elevated blood pressure = wine, cheese, cured meat
Avoid drinking ___ juice while taking most prescription drugs
grapefruit
> The molecule bergamottin, which is found in grapefruit, can inactivate drug-metabolizing enzymes in the liver, which allows drug levels to build up in the bloodstream
Gender:
Males and females may differ in specific drug pharmacokinetics and pharmacodynamics
Gender differences in drug response may affect drug safety and effectiveness
Special attention should be paid to drugs known to behave differently in pregnancy
Pregnancy-induced changes in drug pharmacokinetics
You are conducting a physical therapy evaluation for a patient that has experienced an electrical burn. The burn wound appears charred and you see that the epidermis, dermis, subcutaneous tissues, and muscles have been destroyed. How should this patient’s burn wound be classified?
Deep partial-thickness burn – 3rd degree
Full thickness-Subdermal burn – 4th degree
Superficial partial-thickness burn – 2nd degree
Epidermal burn – 1st degree
A: Full thickness - Subdermal burn – 4th degree
A subdermal burn is a burn that appears charred and the epidermis, dermis, subcutaneous tissues and muscles have been destroyed. This type of burn can heal with skin grafting and scarring, but it will require extensive surgery and amputation is sometimes required.
