Transcript Pharmacokinetics

Pharmacokinetics
Insulin
C254H377N65O76S6
1. Discuss the four main processes that make up pharmacokinetics
(absorption, distribution, metabolism, and excretion), and
appropriately apply these processes to clinical usefulness.
2. Discuss the advantages and disadvantages of the various
techniques of drug administration as they relate to
pharmacokinetics, noting especially any barriers to absorption
associated with intravenous, intramuscular, and oral administration.
Students should also compare oral administration with parenteral
administration.
3. Describe blood flow to tissues, the ability of a drug to exit the
vascular system, and the ability of a drug to enter cells, and then
discuss characteristics of drug molecules that can alter these
processes.
4. Compare drugs with short half-lives to those with long half-lives.
Discuss the negative effects of repeated drug doses.
5. Discuss the consequences of drug blood levels that fluctuate
considerably or erratically between doses, and describe how nurses
identify such fluctuations. Discuss measures that traditionally are
used to minimize fluctuation.
6. Describe the ultimate “goal” of drug metabolism, also known as
biotransformation. Discuss the general processes involved in drug
metabolism, and describe in what major/vital organs most drug
metabolism occurs. Discuss special considerations in drug
metabolism.
7. Discuss the importance of excretion of a drug from the body and
some of the routes from which the drug may be excreted.
8. Discuss the importance of understanding the time course of drug
responses (plasma drug levels, single-dose time course, drug halflife, and drug levels produced with repeated doses). Explain why
clinicians often monitor plasma drug levels, and describe how these
levels are regulated to prevent drug toxicity. Identify the two factors
that largely determine the duration of a single-dose time course, and
compare drugs with short half-lives to those with long half-lives.
Discuss the negative effects of repeated drug doses.
9. Discuss the consequences of drug blood levels that fluctuate
considerably or erratically between doses, and describe how nurses
identify such fluctuations.
10. Discuss measures that traditionally are used to minimize
fluctuation.
Pharmakon (drug or poison)
Kinesis (motion)
Pharmacokinetics
(the study of drug movement
throughout the body)
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By applying knowledge of
pharmacokinetics to drug therapy, we
can help maximize beneficial effects and
minimize harm.
* If you can nail this chapter, the rest is a breeze.
* Understanding this chapter is key.
All phases of pharmokinetics involve
movement across the cell
Three ways to
cross a cell
membrane
Channels and
pores
Transport
systems
P-glycoprotein
Direct
penetration of
the membrane
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Very few drugs cross
the membrane using
this means.
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Channels are very
small & highly specific
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Only smallest
molecules can pass &
only if it is the right
channel
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Carrier systems that
can move drugs from
one side of the
membrane to another
Some require energy,
some do not
All are selective –
depends on the drug
structure
** Superstar →
P-glycoprotein
* Transmembrane
protein that transports a
wide variety of drugs
* Present in the liver,
kidneys, placenta,
intestines and the
capillaries of the brain
Most common – why?
How is this possible?
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Most drugs too big to
fit through channels or
pores
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Drugs must be
lipophilic (lipid
soluble)
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Most drugs lack
transport systems
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Some molecules are
not lipophilic and can
not cross the
membrane →
Polar molecules
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Molecules with
uneven distribution
of electrical charge
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No net charge
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Equal number of
protons & electrons
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Like dissolves like
water molecule
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Molecules that have a
net charge
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Only very small ions
are able to cross
membranes
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Molecules that have at
least one atom of
Nitrogen
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Carry a +ve charge at
all times
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Unable to cross most
membranes
Eg. Turbocurarine
(Curare)
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Certain drugs can exist
in charged or
uncharged forms
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Many drugs exist as
weak organic acids or
weak organic bases.
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Who’s your neighbour?
Acids tend to ionize in
basic media
Bases tend to ionize in
acidic media
e.g. Aspirin
(acetylsalicylic acid)
(stomach & gut)
Acetaminophen
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pH across the
membrane
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Drug molecules tend to
gather on the side of
the membrane where
the pH most favours
ionization
Acids like to hang out on
the basic (alkaline) side
• Bases hang out on the
acidic side
=
Ion trapping (pH partitioning)
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Where’s the party?
The movement of a drug from its site of
administration into the blood
* Rate of absorption determines how soon effects
will begin
* Amount of absorption helps determine how
intense the effects will be.
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Factors affecting drug absorption
Characteristics of commonly used routes of
administration
Pharmaceutical preparations for oral
administration
Additional routes of administration
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Rate of dissolution
Surface area
Blood flow
Lipid solubility
pH partitioning
See Table 4-1 Properties of Major Routes
of Drug Administration (Lehne, p.32)
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Intravenous
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Barriers to absorption
Absorption pattern
Advantages
Disadvantages
Intramuscular
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Barriers to absorption
Absorption pattern
Advantages
Disadvantages
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Subcutaneous
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No significant barriers to absorption
Oral
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Barriers to absorption
Absorption pattern
Drug movement following absorption
Advantages
Disadvantages
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Tablets
Enteric-coated preparations
Sustained-release preparations
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Topical
Transdermal
Inhaled
Rectal
Vaginal
Topical
- Peripheral tissue
activity
- Systemic side effects
less likely
- If analgesic, applied
directly over painful site
- Insignificant serum
levels
Transdermal
- Systemic activity
- Potential for adverse
effects
- If analgesic, may be
applied away from
painful site
- Serum levels necessary
for effect
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The movement of drugs throughout the
body
Drug distribution is
determined by
these three factors
• Blood flow to
tissues
• Exiting the
vascular system
• Entering cells
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Drugs are carried by the blood to tissues and
organs of the body
Abscesses and tumors
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Low regional blood flow impacts therapy
Pus-filled pockets, not internal blood vessels
Solid tumors have limited blood supply
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Typical capillary beds
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Drugs pass between capillary cells rather than
through them
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Tight junctions between the cells that compose
the walls of most capillaries in the CNS
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Drugs must be able to pass through cells of the
capillary wall
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Only drugs that are lipid soluble or have a
transport system can cross the BBB to a
significant degree
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Membranes of the placenta do NOT constitute
an absolute barrier to the passage of drugs
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Movement determined in the same way as other
membranes
Risks with drug transfer
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Birth defects: mental retardation, gross
malformations, low birth weight
Mother’s use of habitual opioids: birth of drugdependent baby
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Drugs can form reversible bonds with
various proteins.
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Plasma albumin is the most abundant and
important.
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Large molecule that always remains in the
bloodstream
Impacts drug distribution
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Some drugs must enter cells to reach site of
action.
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Most drugs must enter cells to undergo
metabolism and excretion.
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Many drugs produce their effects by binding
with receptors on external surface of the cell
membrane.
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Do not need to cross the cell membrane to act
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Also known as biotransformation
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Defined as the enzymatic alteration of drug
structure
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Most often takes place in the liver
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Hepatic drug-metabolizing enzymes
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Therapeutic consequences of drug metabolism
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Special considerations in drug metabolism
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Most drug metabolism that takes place in the
liver is performed by the hepatic microsomal
enzyme system, also known as the P450 system.
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Metabolism doesn’t always result in a smaller
molecule.
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Accelerated renal drug excretion
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Drug inactivation
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Increased therapeutic action
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Activation of prodrugs
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Increased or decreased toxicity
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Age
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Induction of drug-metabolizing enzymes
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First-pass effect
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Nutritional status
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Competition between drugs
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Defined as the removal of drugs from the body
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Drugs and their metabolites can exit the body
through:
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Urine, feces, air, sweat, saliva, breast milk, or
expired air
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Steps in renal drug excretion
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Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Factors that modify renal drug excretion
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pH-dependent ionization
Competition for active tubular transport
Age
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Breast milk
Other non-renal routes of excretion
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Bile
Enterohepatic recirculation
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Lungs (especially anesthesia)
Sweat/saliva (small amounts)
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Plasma drug levels
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Single-dose time course
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Drug half-life
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Drug levels produced with repeated doses
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Clinical significance of plasma drug levels
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Two plasma drug levels defined
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Minimum effective concentration
Toxic concentration
Therapeutic range
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The objective of drug dosing is to maintain
plasma drug levels within the therapeutic
range.
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The duration of effects is determined largely by
the combination of metabolism and excretion.
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Drug levels above MEC – therapeutic response
will be maintained.
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Defined as the time required for the amount of
drug in the body to decrease by 50%
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Percentage vs. amount
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Determines the dosing
interval
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The process by which plateau drug levels are
achieved
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Time to plateau
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Techniques for reducing fluctuations in drug
levels
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Loading doses vs. maintenance doses
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Decline from plateau