Lecture 2 and 3 - Pharmacokinetics Flashcards
What is pharmacokinetics?
The study of how the body absorbs, distributes, metabolizes, and eliminates a drug over time
What is the primary site of absorption?
Small intestine
What is the primary site of excretion?
Kidneys
What is the primary site of metabolism?
Liver
What is the primary site of distribution?
Bloodstream
What is the clinical goal of pharmacokinetics?
Enhancing efficacy and decreasing toxicity
What is a better name for metabolism?
Biotransformation
What are the fastest routes of administration?
IV, inhalation, and sublingual
What are the slower routes of administration?
Transdermal and subcutaneous
What do drugs need to cross to move through the body?
Cell membranes
How do drugs cross cell membranes and which is the most common method?
- Pass through channels or pores
- Pass through the membrane with the aid of a transport system
- Penetrate directly (most common)
Where are transporters found and what do they do?
- Liver, kidneys, intestines, brain capillaries
- Transport a variety of drugs across membranes
Why do most drugs penetrate membranes directly?
- Most drugs are too large to pass through channels
- Most drugs lack transport system to help them cross cell membranes
A drug must be ____ to penetrate cell membranes directly
Lipid soluble
What is the one-compartment model of drug disposition?
The drug does not extensively distribute into extravascular tissues
What is the two-compartment model of drug disposition?
The drug is administered to the central portion of the body, and then moves to the periphery
What is an example of a drug that demonstrates the one-compartment model?
Aminoglycosides
What is an example of a drug that demonstrates the multi-compartment model?
Benzodiazepines
What is bioavailability?
The fraction of unchanged drug reaching the systemic circulation following administration by any route
How are drug accumulation and dose lost related?
They are inversely proportional
What is volume of distribution?
The measure of the apparent space in the body available to contain the drug
What is clearance?
The measure of the ability of the body to eliminate the drug
What is a half-life?
The time required to change the amount of drug in the body by one-half during elimination
How do you calculate bioavailability?
(AUC admin route/AUC iv) * 100
How do you calculate drug accumulation?
1/ dose lost
How do you calculate volume of distribution?
Amount of drug in body (mg) / concentration of drug in plasma (mg/L)
How do you calculate clearance?
(0.693/t 1/2) * Vd
How you calculate half-life?
(0.693 * Vd) / Cl
What are 3 values that determine drug absorption?
1) Time to peak concentration (rate)
2) Peak concentration (rate and extent)
3) Area under the plasma concentration vs. time curve
What does the area under the plasma concentration (AUC) determine?
- The extent of absorption of the drug
- The actual body exposure to the drug
Which route of administration have 100% bioavailability?
IV
What are 3 limitations for drug absorption?
1) Tissue perfusion
2) Diffusion-limited absorption
3) First pass effect
What is first pass effect?
Rapid liver inactivation of oral drugs
What is the advantage to enterohepatic cycling?
- Reduces elimination
- Prolongs t 1/2
What are some factors that influence drug absorption?
- Formulation
- Water and lipid solubility
- GI motility
- Posture
- Other drugs/foods
- pKa
- Gastric pH
When will an acidic drug be ionized and non-ionized?
Ionized in alkaline media and non-ionized in acid media
What can the Henderson-Hasselbalch equation be used for determining?
How much drug on each side of membrane
What is steady state?
When the rate of drug elimination equals the rate of administration
Which route of administration can attain steady state?
IV infusion
Which protein is the most common for bound drugs?
Albumin
Can bound or unbound drugs leave vessels?
Unbound b/c bound drugs are too big
What can be altered when a high quantity of a drug is bound?
Distribution time
What factors affect volume of distribution?
Solubility, charge, size
What is volume of distribution important for?
- Determining clearance of a drug from the body
- Determining loading dose of a drug
What does a high Vd mean?
That the drug is not staying in the vascular compartment (it is extensively distributed)
Can Vd surpass body fluid volume?
Yes
How do you calculate loading dose?
Vd * desired plasma concentration
How do you calculate dosing rate?
- Clearance * target plasma concentration
- Amount / time
How do you calculate maintenance dose?
(dosing rate / F) * dosing interval
What are some factors that influence drug distribution in the body?
- pKa of compound and pH of tissue compartment
- Drug binding
- Specialized distribution barriers (BBB, placenta)
Where are acidic drugs more likely to be concentrated?
In blood compartment
Where are basic drugs more likely to be concentrated?
Tissue
Drug metabolites are usually more _____ than their parent compound
Polar
What can happen with the ingestion of 2 or more drugs?
It can affect the rate of metabolism in one or both drugs
What are phase 1 reactions?
Oxidation, reduction, and hydrolysis reactions
What are phase 2 reactions?
Glucuronidation, sulfation, and acetylation reactions
When do phase 1 reactions take place?
Between absorption and metabolism
When do phase 2 reactions take place?
Metabolism and elimination
Most drugs are ____ order
First
What is first order metabolism?
When the rate of drug metabolism is proportional to dose
What is zero order metabolism?
When the rate of drug metabolism remains constant over time
What is the importance of clearance?
Provides an index of the efficiency by which a drug is removed from the body
What factors can cause clearance to change?
- Disease state
- Genetic and environmental factors
What is clearance needed for determining?
Dosing rate and maintenance dose
How many half-lives are required to eliminate a single dose of a drug from the body?
Around 5
Do high or low MW drugs enter the kidney?
Low
What does the kidney filter back into the blood and what does it keep in the urine?
- Filters lipid soluble drugs into the blood
- Keeps non-lipid soluble, polar, and ionized drugs in the urine
What are the 3 steps of renal elimination?
1) Glomerular filtration
2) Tubular reabsorption
3) Tubular secretion
What is used to assess renal impairment?
Creatinine clearance
What are some examples of drug transporters?
1) Organic anion transport proteins
2) Organic cation transport proteins
3) P-glycoprotein
4) Multidrug resistance-associated proteins (MRP)
Bile excretion favours compounds with _____ MW
Higher
What is a prodrug?
The inactive form of a drug
How does a prodrug become active?
Through metabolism
Does a prodrug increase or decrease bioavailability and why?
Increases because it prevents the drug from undergoing first pass metabolism
What happens if a drug becomes associated with fat?
It alters distribution and elimination
Which group of enzymes metabolizes drugs in the liver?
Microsomal enzyme system, or P450 system
How many families make up the P450 system?
12
What do the 12 families of the P450 system do?
- 3 families metabolize drugs (CYP 1, 2, 3)
- 9 families metabolize steroids and fatty acids
What are the 2 most prevalent CYP enzymes?
CYP 3A4 and 3A5
What does CYP 2D6 do?
Metabolizes morphine and codeine
What are 3 main substrates of CYP 3A4?
Acetaminophen, cocaine, and testosterone
What is one main inducer of CYP 3A4?
St. John’s wort
What is one main inhibitor of CYP 3A4?
Grapefruit juice
What is the importance of phenytoin with respect to CYP enzymes?
Over time phenytoin causes an increased expression level for CYP 3A4
What does rifampicin do to CYP450 enzymes?
Induces them
How do CYP enzymes get induced?
Drug binds to a site on the gene encoding the enzyme which turns on synthesis of more enzyme
What does xenobiotic mean?
Any foreign substance you ingest
Can the induction mechanism change in response to environment?
Yes
What is the importance of induction with respect to pharmacokinetics?
Increased clearance and decreased half-life
What is the important of induction with respect to pharmacodynamics?
Decreased response
Are CYP enzymes only induced by drugs?
No, they can be induced by environment/lifestyle factors and herbal/nutritional supplements
Smoking has an effect on ______ and ______ of drugs
Clearance and metabolism
What is the importance of cimetidine with respect to CYP enzymes?
It is a potent inhibitor of several CYP enzymes
What are 4 drug interactions with cimetidine?
- Warfarin
- Benzodiazepines
- Phenytoin
- Morphine
What is the importance of inhibition with respect to pharmacokinetics?
Decreased clearance and increased half-life
What is the important of inhibition with respect to pharmacodynamics?
Increased response and duration
For an inhibitor, are effects immediate or delayed?
Immediate
For an inducer, are effects immediate or delayed?
Delayed
How can you reduce the risk of interactions?
Reduce the number of drugs
What are the 3 polymorphisms of some CYP enzymes?
- Poor metabolizer
- Extensive metabolizer
- Ultra-extensive metabolizer
What does a poor metabolizer mean?
Increased toxicity
What does an ultra-extensive metabolizer mean?
Reduced response
What does an extensive metabolizer mean?
Normal response
In which age groups in rate of drug disposition most likely impaired?
Very young and very old
What needs to be modified in a patient who has a disease that impairs organ function?
Dosage
