Pharmacokinetics Flashcards
What are the 4 main components of pharmacokinetics?
ADME: absorption, distribution, metabolism, excretion
True or false: measured plasma drug concentration usually reflects TOTAL drug concentration in the plasma regardless of whether it is bound to proteins or other plasma constituents.
true
What is the Area Under the Curve used for?
- to compare the amount of drug that reaches the systemic circulation by different routes of administration (bioavailability)
- to compare clearance of a drug in different patients after administering same dose
How is bioavailability (F) related to AUC?
F=(AUCoral/AUCiv)x100
Describes the process by which drugs move from their site of administration to the plasma.
drug absorption
What is the main site of absorption of most orally administered drugs and why?
small intestine due to large surface area (even larger than the stomach)
What are some factors affecting drug absorption?
- chemical comp. of drug and delivery formulation
- regional blood flow differences
- transport mechanisms
- permeability characteristics
- ion trapping
- nonspecific binding
- surface area
Lipid solubility of a drug is dependent upon _________.
degree of ionization (which depends upon pH of solutions and pKa of drug)
In terms of ionization state, which form of a drug is the most lipid soluble?
non-ionized form
Explain the first-pass effect.
Some drugs are highly metabolized when they pass through the liver, so only a fraction of the absorbed drug reaches the systemic circulation (=bioavailability).
How does enterohepatic circulation affect drug absorption?
With enterohepatic circulation, drugs may be secreted into the bile and reabsorbed via the small intestine. This can delay delivery to the systemic circulation and reduce bioavailability.
What is the bioavailability of a drug?
the fraction of the administered dose that reaches the systemic circulation in its active form
When would a drug have less than 100% bioavailability?
if it is incompletely absorbed or undergoes metabolism (ex: in liver)
What are the components of first-pass metabolism?
- intestinal
- hepatic
What are the advantages of sublingual drug administration?
- it bypasses the portal circulation and therefore avoids first-pass metabolism
- higher pH may be beneficial for absorption of more basic drugs
What is parenteral drug administration?
injection of drugs into tissues or directly into vasculature
What maintains the concentration gradient with parenteral drug administration?
blood flow, so drug absorption is faster in more highly vascularized tissues (ex: skeletal muscle)
What are examples of parenteral drug administration?
- subcutaneous
- intramuscular
- intravenous
What are the methods of enteral drug administration?
- oral
- sublingual
- buccal
- rectal
What is the advantage of rectal drug administration?
- 50-60% of the absorbed drug bypasses portal circulation, thereby avoiding first pass metabolism
- useful in cases of nausea and vomiting
What is the basis of pulmonary drug delivery?
- absorption via passive diffusion
- facilitated by large alveolar surface area
Highly _______ forms of drugs may reach systemic circulation.
lipid-soluble
What is the basis of transdermal drug administration?
passive diffusion of drugs across the skin, driven by a concentration gradient; intended for controlled release of drug into systemic circulation
What are the major limitations of transdermal drug administration?
- skin barrier limits # of drugs that can be delivered via passive diffusion
- potential skin irritation
What are the main advantages of parenteral drug administration?
- absorption unaffected by food in stomach
- no first-pass effect
- greater degree of reliability/precision of administered dose
What is one of the major downfalls of subcutaneous drug administration?
It is ineffective when peripheral circulation is impaired, such as in cases of shock.
What is the fastest and most reliable means of achieving a defined blood level of a drug?
intravenous
What are the factors influencing distribution of absorbed drugs?
- regional differences in blood flow
- tissue mass
- transport mechanisms
- permeability characteristics
- ion trapping
- protein binding
True or false: Drugs can only distribute to tissues when UNbound by plasma proteins.
true
Describe volume of distribution (Vd).
It is a measure of how evenly distributed a drug is in the body, and it is one of the primary pharmokinetic properties. It represents the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the initial concentration of drug remaining in the plasma.
Volume of distribution relates _______ to _______ of a drug.
dose (amt.); plasma concentration
Vd=dose/conc. @ t=0
What are examples of tissues that act as drug reservoirs?
fat and muscle
What is the implication of drug reservoirs?
More of a drug may be stored in certain tissues than remains in the systemic circulation. Thus gradual release of drug from these sites may prolong the therapeutic effect or result in toxicity.
Aside from fat and muscle, what else can act as a drug reservoir?
plasma proteins
Which 3 variables are used to calculate loading dose?
- Cp (peak desired drug concentration)
- Vd (volume of distribution of drug in body)
- F (bioavailability)
What is maintenance dosing?
a dosing strategy to maintain a steady state of drug in the body, based on replacing the amount of drug cleared from the body since the previous drug administration
What is the primary determinant for calculating maintenance dose?
clearance
What is the primary determinant for calculating the loading dose?
Vd
What is the difference between elimination clearance and intercompartmental clearance?
elimination clearance is irreversible drug removal from the plasma through an eliminating organ, while intercompartmental clearance is bidirectional drug distribution between plasma and tissues
When is a loading dose used?
If a drug takes a long time to reach therapeutic levels. The loading dose is a higher dose given initially before dropping down to a lower maintenance dose.
Is the amount of time to reach steady state reduced by the loading dose?
NO! A loading dose will not decrease the time to steady state… it will only get us back to therapeutic range quicker.
Describe what a steady state is in pharmacokinetics.
when rate of drug administration=rate of drug elimination
Time to steady state is [dependent/independent] of dosage.
independent
What are fluctuations in drug plasma concentration proportional to?
dosage interval / HL (longer interval=greater fluctuation)
Steady state concentration is [directly/inversely] related to clearance/bioavailability.
inversely
Steady state concentration is proportional to_________.
infusion rate (dose/dosage interval)
True or false: zero-order drug elimination is proportional to drug concentration.
False! It is only proportional to the elimination constant.
What are the classic examples of drugs with zero-order elimination?
aspirin, phenytoin, and ethanol
Is half life constant with zero-order kinetics?
no!
List examples of drugs that may exhibit zero-order kinetics (aside from the major 3).
heparin, phenylbutazone, salicylates, theophylline, tolbutamide, warfarin
What is elimination half-life?
the time to eliminate 50% of the body content of the drug (t1/2=0.69Vd/CL)
*only applies to first-order kinetics!
What are the units for elimination clearance?
ml/min or L/hr
What is the salt factor (and what is the reason for it)?
- salt factor is the fraction of total drug that will be delivered as active drug to the systemic circulation
- in rare cases, a drug may be prepared in a formulation that provides a fraction of the total weight of drug as active drug and the remainder as inactive salt
What must we take into account when dosing by different routes of administration?
adjustments for bioavailability (different routes may have different bioavailabilities)
For patients with renal insufficiency, how can the dosing RATE be reduced?
- by reducing the dose
- by increasing the dosing interval
- both
What is the Cockcroft and Gault formula used for?
to estimate creatinine clearance, which can be used to adjust drug dosing in a patient with renal failure
What are the determinants of hepatic drug clearance?
- hepatic blood flow
- plasma protein binding
- intrinsic clearance
What are some examples of drugs with restrictive hepatic clearance?
warfarin and phenytoin
What will have the greatest effect on hepatic clearance for drugs with restrictive hepatic clearance?
changes in protein binding or drug metabolism/excretion activity, as opposed to liver blood flow (capacity-limited)
