Uptake and Distribution of IV Agents Flashcards
Pharmacokinetics consist of?
absorption distribution metabolism excretion "What the body does to a drug"
Pharmacodynamics consist of?
mechanism of effect
sensitivity
responsiveness
“what a drug does to the body”
What are common parameters of pharmacokinetics?
elimination of half-time
bioavailability
clearance
volume of distribution
The body is divided into what 2 compartments?
Central and Peripheral
The central compartment is made up of what?
- Highly perfused tissues: kidney, liver. heart, brain receive 75% of the CO, represents only 10% of the body mass
- Rapid uptake of drug
How is the drug distributed?
drug first introduced into the central compartment distributes to the 2nd compartment and returns to the central compartment for clearance
The peripheral compartment is made up of what?
- large calculated volume
- extensive uptake of drug
Rate of transfer between compartments…
decreases with aging, leading to greater plasma [ ] in certain drugs (thiopental)
What is the volume of distribution?
sum of all the volumes of the compartments
Vd = dose of IV drug/plasma [ ] before elimination
Vd is influenced by what physiochemical characteristics of the drug?
lipid solubility
binding to plasma proteins
molecular size
What is the elimination of half-time?
the time necessary for the plasma [ ] of drug to decline 50% during the elimination phase
E1/2t of a drug is directly proportional to ______ and inversely proportional to its ______.
Vd; clearance
T/F: Elimination half-time is independent of the dose of the drug administered.
True
How does drug accumulation occur?
if the dosing intervals are less than the elimination half times
What is the relationship of half-times to the fractional amount remaining to the amount eliminated, respectively?
halftimes—remaining—eliminated
0---1------0 1---1/2----50 2---1/4----75 3---1/8----87.5 4---1/16---93.8 5---1/32---96.9 6---1/64---98.4
As the plasma [ ] of drug decreases below that of highly perfused tissues….
drug leaves and is redistributed to less well-perfused sites, i.e. muscle and fat
With continuing elimination of the drug, the plasma [ ] declines below that in the tissues…
drug leaves tissues to re-enter the circulation
What happens when tissues accumulate drug?
tissues that accumulate drug preferentially act as a reservoir to maintain the plasma [ ] and prolong effect
Large or repeated doses..
saturate inactive tissue negating, redistribution, again prolonging duration of action, as now reduction of effect depends on metabolism rather than redistribution
What does absorption depend on?
regardless of the route of drug administration, depends on the drug’s solubility
Oral administration
most convenient and economic
What are disadvantages of oral administration?
emesis, destruction by enzymes or acidic gastric fluid, irregular absorption with food or other drugs
What the is first pass effect?
drugs absorbed from the GI system, enter the portal venous blood and pass through the liver before entering the systemic circulation for delivery to tissue receptors. Here they are extensively extracted and metabolized
Sublingual, transmucosal absorption
rapid onset; bypasses the liver and prevents first pass effect
Transdermal absorption..
provides sustained therapeutic plasma [ ]
Where does the absorption occur with transdermal?
- occurs along sweat ducts and hair follicles that function as diffusion shunts
- rate limiting step is diffusion across the stratum corneum of the epidermis
- thickness and blood flow are factors reflected in the skin’s permeability for drugs
- contact dermatitis can occur at the site
Rectal absorption..
- proximal rectum - transport to the portal system via superior hemorrhoidal veins, thereby first pass effect
- distal rectum - bypasses portal system
IV absorption..
achieve therapeutic plasma levels precisely and rapidly
Lung uptake..
lung uptakes basic lipophilic drugs and acts as a reservoir to release drug back into the systemic circulation
(lido, fentanyl, demerol)
T/F: BBB prevents ionized, water soluble drugs from crossing the barrier.
True
Under what circumstances can the BBB be overcome?
large doses of drug
head injury
hypoxemia
Non-ionized drugs are usually ____ soluble and ____ diffuse across lipid cell membranes.
lipid; can
What are some examples of lipid cell membranes?
BBB, renal tubules, GI epithelium, hepatocytes
Degree of Ionization
- depends on its dissociation constant (pK) and the pH of the surrounding fluid
- changes in pH can result in large degree of ionization, i.e. acidic drugs are highly ionized at alkaline pH, and vice versa
Ion trapping
[ ] difference of total drug can develop on two sides of a membrane that separates fluids with different pHs, i.e placenta
Protein Binding
most drugs bind in various degrees; only free or unbound fraction of drug is readily available to cross cell membranes
-unbound also metabolized and excreted more readily
Drugs that are highly protein bound..
are markedly effected by alterations in protein binding
What are examples of drugs that are highly protein bound?
warfarin, propranolol, phenytoin, diazepam
What is clearance?
volume of plasma cleared of drug by metabolism and excretion
What is First-Order Kinetics?
almost all drugs administered in therapeutic dose ranges are cleared at a rate proportional to the amount of drug present in the plasma
What is Zero-Order Kinetics?
a few drugs will exceed the metabolic or excretory capacity of the body to clear drugs by first order kinetics even at therapeutic doses
- constant amount of drug is cleared per unit of time
i. e. ASA, dilantin, ETOH
Hepatic Clearance
determined by hepatic blood flow and hepatic extraction
“Perfusion-dependent elimination”
If hepatic extraction for a drug is high (greater than 0.7) the clearance of the drug will depend on hepatic blood flow
“Capacity-dependent elimination”
if the hepatic extraction ratio is low (less than 0.3) a decrease in protein binding or an increase in enzyme activity will increase hepatic clearance
-changes in hepatic blood flow will have minimal changes in its clearance
Renal Clearance
- most important organ for elimination of unchanged drugs or their metabolites
- water-soluble compounds are excreted more efficiently by the kidney’s than lipid soluble
Highly lipid soluble drugs are ______ such that little or no unchanged drug is ____ in the urine/
reabsorbed; excreted
What is metabolism?
biotransformation to convert pharmacologically active, lipid soluble drugs into water soluble and often inactive drugs.
Increased water solubility _____ the Vd for a drug and ______ its renal excretion.
reduces; enhances
What are the 4 pathways of metabolism?
oxidation
reduction
hydrolysis
conjugation
Hepatic Microsomal Enzymes
located in hepatic smooth ER
Cytochrome P-450
large number of different protein enzymes involved in oxidation and reduction and conjugation of a large number of drugs
What are the 6 well characterized forms (isozymes) of the cytochrome P-450 system involved in drug metabolism in humans?
CY1A2 CYP2D6 CYP2C19 CYP2E1 CYP2C9 CYP3A
Enzyme induction
drugs and chemicals stimulate activity of these enzymes (i.e. zero-order kinetics)
Nonmicrosomal Enzymes
- metabolize drugs mostly by conjugation and hydrolysis
- to a lesser degree by oxidation
- hydrolysis of drugs that contain ester bonds (sux, esmolol)
- do NOT undergo enzyme induction
- determined genetically
Where are nonmicrosomal enzymes located?
liver mostly, plasma, GI tract
What is the most common mechanism by which drugs exert pharmacologic effect?
by their interaction with specific macromolecules in the lipid bi-layer of cell membranes called receptors
Receptors can _____ or ____ in number in response to specific stimuli
increase; decrease
State of Receptor Activation Theory
non-activated receptors are converted to active by the drug
Receptor Occupancy Theory
The more receptors occupied by drug the more effect
Nonreceptor Drug Action
mechanisms other than receptor-drug interactions i.e. chelating drugs from bonds with metallic cations that may be found in the body
How do antacids neutralize gastric acid?
direct action
Agonist drugs
mimic cell signaling molecules by activating the same receptor sites and causing similar effects
Antagonist drugs
bind to receptors as well and change the configuration of agonist site or bind to it, preventing effect from cell signaling molecules
Structure activity
the affinity of a drug for a specific macromolecular component of the cell and its intrinsic activity are intimately related to its chemical structure
-subtle changes as stereochemistry, may result in major changes in pharmacological properties
What is elimination half-life?
time necessary to eliminate 50% of the drug from the BODY
When is elimination half-time and elimination half-life not equal?
when the decrease in the drug’s plasma [ ] does not parallel its elimination form the body
Most drugs are weak ___ or weak _____;present in both ______ and _______ forms
acids;bases;ionized;non-ionized
T/F: In the ionized form, the drug can cross membranes.
FALSE
in the ionized form it cannot cross
Ionized fraction of the drug is excreted by the kidneys _____.
unchanged
Which fraction of drug is considered active?
non-ionized
Non-ionized is metabolized by..
the liver
Phase I metabolism
oxidation, reduction, hydrolysis
Phase II metabolism
parent or metabolite drug reacts with an endogenous substrate to form water-soluble conjugates
What are the sites for metabolism?
kidneys, lungs, GI tract and
liver- hepatic microsomal enzymes are responsible for metabolism for most drugs
Stereochemistry
- enantemerism can be produced by sp3 hybridized carbon atoms
- free rotation about the chiral carbon is not possible, two stable forms of the molecule exist
- interaction with biological receptors can differ greatly between two enantomers
- some isomers may cause entirely different effects
Hyper-reactive
people in whom unusually low dose of drug produces its expected pharmacologic effect
Hypersensitivity
immune response, people who are allergic
Additive effect
second drug acting with the first will produce equla to the sum of both
1+1=2
Synergetic effect
two drugs interact to produce an effect greater than their sum
1+1=3
How is the Vd of a drug related to its lipophilicity, amount bound to plasma proteins, and molecular size?
directly proportional to lipophilicity
indirectly proportional to both amount bound to plasma proteins and molecular size
Half-time is related to eliminated a drug from the ___________, while half-life is related to eliminating it from the ______________.
plasma; body
Quick overview:
Acids are proton ___________and bases are proton_________.
The degree of ionization of an agent is determined by its dissociation __________ and the ___________ gradient across the membrane.
donors; acceptors
pKa; pH
If a medication is a weak base, what happens if:
pH>pKa
pH=pKa or pH is less then pKa
pH>pKa= unionized form predominates
pH=pKa=unionized =to ionized
pH is less then pKa=ionized form predominates
If a medication is a weak acid, what happens if:
pH>pKa
pH=pKa or pH is less then pKa
pH>pKa=ionized form predominates
pH=pKa=unionized form = to ionized
pH is less then pKa=unionized form predominates
The ____________ for a specific agent can vary across a membrane that separates fluids w/ different pH values
degree of ionization
If morphine is a base and in the blood and has a pKa of 7.9, and then enters the stomach, what is likely to happen?
ion trapping: stomach has a much lower pH then the blood (1.9 versus 7.4) so when morphine enters the stomach, the morphine (a base) accepts protons and becomes ionized, thus becoming trapped
What 2 situations can influence a drug’s clinical effect related to its protein binding capacity?
- reduction of body proteins (malnourished; liver disease; last trimester of pregnancy)
- drug interaction between 2 or more highly protein-bound drugs
Albumin generally binds to _________ drugs while alpha1-acid glycoproteins generally bind to ________drugs.
acidic, basic
Drug that is protein-bound doesn’t have effect on the body but can contribute to _______________
duration of effect
If a drug that is highly protein bound (more than 90%) i.e. warfarin, is displaced from the plasma protein, what could happen?
Why is this not always seen?
intensification of its effect
not always seen because as the amount of unbound drug increases, so does its elimination
What types of drugs are best absorbed from the oral route?
acidic drugs, i.e. barbituates; they remain unionized and t/f are easily absorbed
Three mechanisms cause pre-systemic elimination of oral drugs. What are they?
hydrolysis in the stomach
enzymes in GI tract deactivate
first-pass effect
What is bioavailability?
the extent to which a drug reaches its effect site after its introduction to the circulatory system
The rate at which systemic absorption occurs establishes a drug’s ___________ and __________
duration of action and intensity
What types of drugs will have large Vd and low plasma concentrations?
drugs that are free, unbound to proteins, and lipid soluble
The Vd is an ____________ variable that allows calculation of a _____________ of a drug if the desired plasma concentration is known
independent
loading dose
Why is the Vd relevant to a drug’s elimination from the body?
b/c drugs can only be eliminated from the body’s organs of elimination (liver, kidneys).
T/f: if a drug has a large Vd but low plasma concentration, very little will be available to the organs of elimination
What are the x and y axises of the plasma concentration curve?
y axis: plasma concentration
x axis: time after dose is injected
Describe the first phase of the plasma conc. curve
alpha phase;
distribution phase
represents the initial dispersal of the drug into the tissue compartments from the central compartment
When is the slope of the alpha phase steep?
when drug is highly lipid soluble: these drugs have the ability to cross membrane lipid bilayers and be distributed to the peripheral compartment rapidly=rapid fall in plasma levels
Describe the 2nd phase of the plasma conc. curve
Beta phase, or elimination phase
reflects elimination of the drug from the circulation by the hepatic, renal and other systems after equilibrium as been reached
slope is flatter and less steep; plateaus
What is the elimination phase of the plasma concentration curve used to determine?
elimination half-life of drugs: important for dosing intervals
What is steady state?
When does this occur?
all body compartments equilibriate w/ circulating agent
tissue concentrations of the drug vary from organ to organ, but they are not changing
elimination = rate at which drug is made available
This occurs w/ chronic administration or continuous IV admin
The end result of phase I reactions is typically a ___________ that is easily excreted by the ________.
more polar compound
kidneys
Phase I reactions enable __________ to occur
phase II
Products of phase II reactions almost always have ___________ biologic activity?
little or no
W/ first order kinetics, a constant _____________ of drug leaves the body over time.
W/ zero order kinetics, a constant __________ of drug leaves the body over time.
1st order: %, or rate
0 order: amount
Clearance is directly proportional to a drug’s _________ and inversely related to its __________ and concentration in the ___________
directly related to: dose
inversely related to: half-life and conc in central compartment
Drugs w/ extraction ratio of 0.7 or higher rely on __________to be cleared while those w/ extraction ratio of 0.3 or lower rely on ___________ to be cleared
perfusion to the liver (pefusion-dependent)
enzymes and degree of protein binding (capacity-dependent)
The amount of drug made available to the renal tubule for elimination depends on ____ and _________
GFR & amount of free unbound drug
The kidneys easily excrete _________ agents, while ____________ agents are usually eliminated by the liver
water-soluble
lipid-soluble
