Pharm: ADME 1 (Overview) Flashcards
Drugs produce their effects as a result of their presence at appropriate ____ at their ____ ____ ____.
concentration at their site of action
The minimum toxic concentration is also referred to as what?
the maximum tolerable concentration
It is the goal of the clinician to maintain drug concentrations where?
in the therapeutic window, which is higher than the minimum effective concentration and the minimum toxic concentration
With IV administration, therapeutic drug concentrations are achieved _____, whereas with oral administration drug concentrations are achieved _________.
rapidly; in delayed fashion
The onset and termination of drug action occurs when?
onset is when the drug concentration rises above the minimum effective concentration, and termination is when it falls below the minimum effective concentration
The decline of drug concentration over time depends on what?
characteristic metabolic and elimination processes associated with the drug
What is the intensity of drug action? (from graph)
the interval that extends from the minimum effective concentration to the maximum concentration achieved; this is variable
Pharmacokinetics is concerned with what?
the fate of the drug within the body, determined by dynamics of drug absorption, distribution, metabolism, and excretion
Absorption is a process reflecting what processes?
the rate at which a drug leaves its site of administration and the rise in drug concentration as it enters the systemic circulation; also describes the extent to which that occurs
Within the systemic circulation, what 2 forms can a drug take? Which form makes the drug available to the tissue?
free or bound form; in free form it is available to bind tissue/cell receptors
What process is responsible for the decline of drug concentration?
metabolism, as it converts drugs to metabolites to be excreted
True or false: free drug can be directly excreted through the process of elimination.
True *(it doesn’t always have to be metabolized first)
The process of distribution involves the movement of drug through/between what?
the systemic circulation, various tissues/sites of action, and sites of elimination
What is the difference between the rising and falling phases of the plasma concentration vs. time plot?
in the rising phase, drug absorption activity is higher than metabolism and excretion; whereas in the falling phase metabolism and excretion are greater than absorption
What two factors are manipulated by the clinician in order to vary the concentration-time profile of a given preparation?
- different doses
2. different administration frequencies
What is the therapeutic index? What do different TI values indicate?
MTC/MEC - min. toxic conc. over min effective conc.
- high ratio - large window, relatively “safe”
- low ratio - use caution to keep drug concentration within the window
What size molecules of drugs may pass through cell membrane pores?
low MW, like 100-200 Da
True or False: cell membranes are permeable to proteins and peptides.
False - they are relatively impermeably to proteins/peptides
Which of the following compounds can pass through cell membranes:
- lipophilic or lipophobic?
- polar or non-polar?
- ionized or non-ionized?
- lipophilic (recall: membranes like higher partition coefficients)
- non-polar
- non- ionized
What are the 3 ways that drugs can be biotransported?
- Passive diffusion
Carrier-mediated biotransport: - Facilitated diffusion
- Active transport
Most drugs pass biological membrane by ____ ____.
passive diffusion
The rate of diffusion is governed by what?
Fick’s law - depends on the distribution of concentrations, size of drug (smaller the better), partition coefficient (lipid solubility), surface area (larger the better), membrane thickness (thinner the better), and ionization (less charged better)
Carrier-mediated biotransport is used for drugs that are too what?
too large or too polar
True or False: transport cycles are irreversible processes of biotransport.
False - they are reversible
Name the carrier-mediated biotransport mechanism that’s an enzymatic process, and therefore subject to saturation.
PLOT TWIST - both are enzymatic processes:
facilitated diffusion AND active transport
Does facilitated diffusion offer movement against a concentration gradient? Does it utilize ATP?
No and No
Does active transport offer movement against a concentration gradient? Does it utilize ATP?
Yes and Yes
Riboflavin and Vitamin B12 use which type of transport across cell membranes?
facilitated diffusion
5-flurouracil uses which type of transport across cell membranes?
active transport
Define, in general terms, co-and counter-transport.
when carrier-mediated transport is coupled to transport of other substances, most notably ions
What is pinocytosis?
It’s the same as endocytosis; can be clathrin-dependent or clathrin-independent
What is the pH-partition theory?
a means to explain the influence of pH and pKa on the extent of the ability of a drug to cross the plasma membrane; assumes that drugs are only absorbed when they are non-ionized (higher lipid solubility)
What supplies the driving force for drug movement across a membrane?
the concentration gradient that exists for the non-ionized form of the drug
Most drugs are strong or weak electrolytes? What does that mean?
weak - meaning that they exist in both charged and uncharged forms in solution
At steady state:
Basic drugs will accumulate on the more ____ side of the membrane, and acidic drugs will accumulate on the more ____ side of the membrane.
Basic drugs –> acidic side
Acidic drugs –> basic side
What is ion trapping?
the phenomenon in which basic and acidic drugs are accumulating on the side of the membrane that has a pH opposite of the drugs’ pH; this represents an important determinant for drug absorption, distribution, and excretion
What is bioavailability?
a clinically relevant parameter referring to the fractional extent to which a given dose of a drug reaches either its site of action or a biological compartment from which the drug has free access to its site of action; ranges from 0 to 1
What phenomenon severely limits the bioavailability of orally administered drugs?
first pass metabolism - metabolism of the drug in the liver which often times inactivates the drug
For all purposes, the bioavailability of IV drugs is given as ____.
1
There are 8 factors listed that modify absorption. Name as many as you can. If you can name them all then you are definitely capable of being a doctor. Or at least a pharmacist.
- route of administration
- circulation to site of absorption
- formulation factors that affect drug solubility
- area of the absorbing surface
- membrane thickness
- drug concentration
- physicochemical factors affecting membrane transport
- transport mechanisms
What are the 2 main branches of drug administration?
- enteral route - via the GI tract (PO, SL, PR)
2. parenteral route - not via GI tract (IV, SQ, IM, IA, Inhal, Top)
How do drugs administered as solids get absorbed?
they must first undergo dissolution, usually occurs in the GI tract
There are many ways to manipulate the drug formulation for absorption advantage. These include:
- delayed or sustained release tablets (enteric coating)
- depot preparations (injection with delayed release)
- rapid release formulations (gel caps)
- transdermal patches
What are the advantages of oral drug administration?
- safe
- cheap
- no need to sterilize (but must be hygienic)
- compact
- multi-dose bottles
- automated machines can produce large quantities
What are the disadvantages of oral drug administration?
- slow onset (usually >1hr)
- patient non compliance
- first pass metabolism –> low bioavailability
The pH of the GI tract is most acidic in the ____ and most basic in the ____.
stomach; intestines
True or false: drugs administered through the buccal cavity will by-pass the liver and avoid first-pass metabolism.
True
What are the 3 main factors affecting GI absorption?
- acidity of stomach
- gastric emptying time
- intestinal motility/transit time
What happens to acidic drugs in the stomach? How is this different from what happens to basic drugs in the stomach?
acidic drugs will be non-ionized and readily enter systemic circuclation, while basic drugs will be ionized and not absorbed until they reach SI
Generally drugs are better absorbed in the ____ (piece of GI tract) because of _________.
small intestine; larger surface area
True or false: increasing gastric emptying will decrease drug absorption.
False - increasing gastric emptying will increase drug absorption, because the drug will be moved to the SI where it is better absorbed
Faster contraction of the small intestine = ____ transit time.
faster
Why does sublingual administration have a rapid absorption time?
the rich blood supply and relatively neutral pH promote absorption
What are the advantages and disadvantages of rectal drug administration?
Advantages: useful in children, unconscious/vomiting patients; no first-pass metabolism
Disadvantages: absorption is erratic; not well accepted by patients
What is the most rapid drug delivery method?
intravenous
What are the advantages of IV drug administration?
- patient compliance (as long as they show up)
- rapid, complete delivery
- no first pass effect
- flexible rate of administration
- vein relatively insensitive to irritation by drugs
What are the disadvantages of IV drug administration?
- expensive - to sterilize, pyrogen test, and make the larger solvent volume
- requires trained personnel
- no recall
- infection risk
- dangerous, toxicity with rapid administration
What are the advantages and disadvantages of subcutaneous (SQ) drug administration?
Advantages: -bypass first pass -varied absorption -can be self-administered Disadvantages: -pain -tissue irritation -volume limited to 2mL
What are the advantages and disadvantages of intramuscular (IM) drug administration?
drugs generally absorbed well due to high blood flow in muscle and lateral diffusion from site of injection; also avoid first-pass
Disadvantages: trained personnel needed, site of injection influences absorption, gender differences, pain, tissue damage, volume limited to 4-5mL
What is intraarterial drug administration?
administered into arteries for delivery to specific organs; requires great care and not only trained personnel but EXPERTS. like an endovascular interventionist.
Intrathecal route is injection into _______ with the purpose of bypassing the ____ and ____. It’s used for what?
subarachnoid space; blood-brain barrier and blood-CSF barrier; used for local effects (like spinal anesthesia) and treatment of acute CNS infections (like meningitis)
Examples of inhalation administration with local effects is ____, and with systemic effects is ____.
bronchodilators; general anesthesia
What are factors to consider (i.e., advantages and disadvantages) in the administration of inhalation agents?
rapid and efficient absorption rate, allergic reaction can occur
True or False: topically administered agents are useful only for local effects.
False - they are useful for local effects but can have systemic effects too.
What are the 3 types of topical routes of administration?
- percutaneous - as in cream, ointment, transdermal patches
- mucous membranes
- eye - like eyedrops
What 3 factors affect the rate of drug distribution?
- cardiac output and regional blood flow
- tissue volume
- capillary permeability
What 4 factors affect the extent of drug distribution?
- physicochemical factors affecting membrane transport
- plasma protein binding
- intracellular binding
- permeability/characteristics of specific tissue membranes
True or False: the greater the blood perfusion rate, the less drug distributed to an organ
False - the greater the blood perfusion rate, the MORE drug distributed to an organ
What organs have the highest perfusion rates? And what does this mean for drug concentration?
brain, kidney, liver, heart; in these organs it would be expected that total drug concentration rises most rapidly
Total blood flow is greatest to which 4 organs/body parts?
brain, kidneys, liver, muscle
What are major factors controlling transcapillary movement of drugs?
lipid solubility & molecular size - because they pass via filtration or passive diffusion through the fenestrated capillary endothelium
Transport of substances >____kD is largely mediated by pinocytosis.
25kD
Which capillaries have larger than normal spaces between endothelial cells?
renal capillaries
Which capillaries have tight junctions between endothelial cells?
brain - this is what makes the BBB
What kinds of compounds can pass the BBB and what can’t?
lipid soluble can, because they can diffuse through cells; polar substances is severely restricted
How does plasma protein limit distribution of free drug to its sites of action?
plasma protein binds the drug, keeping it in the central blood compartment
____ is a plasma protein that binds the widest range of drugs.
Albumin
Acidic drugs commonly bind to ____ (what plasma protein?), while basic drugs commonly bind to ____.
albumin; globulins
Is drug binding to plasma proteins generally specific or non-specific?
non-specific - think about albumin–it binds a ton of stuff. How promiscuous.
True or false: drug binding to plasma proteins is an irreversible process.
False - otherwise, how would the drug ever get off and into its target?
What three factors determine the total fraction of drug bound to plasma proteins?
- drug concentration
- affinity for binding sites
- number of binding sites
At low drug concentrations, the major determinant of the fraction of drug bound to plasma proteins is _________.
affinity of binding sites
At high drug concentrations, the major determinant of the fraction of drug bound to plasma proteins is _________.
the number of binding sites
Because the determinants of drug fraction bound to plasma proteins varies with drug concentration, this entails what?
that binding to plasma proteins is a saturable and nonlinear process
True or false: it is the bound drug that equilibrates with the site of pharmacologic/toxic response.
False - how would that work? No, it’s the FREE drug that equilibrates with the site of pharmacologic/toxic response.
Why does the clinician need to be concerned with the percent bound vs. unbound drug?
because slight changes in the percent free drug can make a difference in the drugs’ effect, especially in drugs with a narrow therapeutic window
Do drugs tend to accumulate in tissues or in EC blood/fluids at higher concentrations?
they tend to accumulate in tissues
Binding of drug to tissue consists of binding either ____ or ____ located ____ or ____, in a process which is generally ____ and ____.
proteins or phospholipids; extracellularly or intracellularly; reversible and saturable
Binding of drug to tissue is dependent on the ____, ____, and ____ ____ of the tissue as well as physicochemical properties of the drug.
concentration, affinity, and binding capacity
What are 4 relevant drug reservoirs?
- stomach - traps basic drugs
- albumin - limits free drug availability
- tissue - liver, thyroid, bone can accumulate drugs
- fat - lipid soluble compounds readily partition into fat tissue
What is an important source of interpatient variability in terms of drug bioavailability?
drug reservoirs, particularly fat tissue
Termination of a drug’s effects usually occurs by ____ and ____, but may also be due to ____.
metabolism and excretion; redistribution
What is a driving factor behind redistribution of drug?
blood flow differences between tissues or organs that see the drug initially
What are the 4 drug distribution patterns?
- vascular system
- body water
- one/more tissues
- non-uniform distribution
What are examples of drugs that distribute largely within the vascular system?
- plasma substitutes such as dextran
- drugs that bind strongly to plasma protein
What is an example of drugs that follow the body water distribution pattern?
low molecular weight water soluble compounds such as ethanol
Most drugs exhibit what type of distribution pattern?
non-uniform, as their distribution is determined by their membrane permeability and lipid/water solubulity
What is volume of distribution (Vd)?
clinically relevant parameter that indicates the apparent body volume that a given drug is located within and is generally indicative of the compartment to which it distributes; often used as a diagnostic tool
How is Vd calculated?
amount of drug administered
- divided by -
plasma drug concentration
How many liters of plasma and of total body water does the average human have?
4L plasma
40L total body water
