Transcript A PRIMER OF DRUG ACTION

Pharmacokinetics: How Drugs
are Handled by the Body
Four Basic Processes in
Pharmacokinetics
• Pharmacokinetics: the study of the
movement of drugs through the body
• Processes:
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Absorption
Distribution
Metabolism
Elimination
Six ways drugs can be
administered
• Orally (swallowed when taken by mouth)
• Rectally (drug embedded in a suppository, which is placed in the
rectum)
• Parenterally (given in liquid form by injection with a needle and
syringe)
• Inhaled through the lungs as gases, vapors, or as particles carried in
smoke or in an aerosol
• Absorbed through the skin (usually as a drugh-containing skin patch)
• Absorbed through mucous membranes (from snorting or sniffing drug)
Oral
• Must be soluble and not destroyed by
gastric juices
• Must be able to cross into blood
• Liquids absorbed faster than tablets
• Can cause upset stomach and vomiting
• Hard to predict how much will be absorbed
Injection
• Three types
– intravenous
– intramuscular
– subcutaneous
• Disadvantages
– rapid absorbtion leaves little time to respond to
unexpected drug reaction or accidental overdose
– requires use of sterile techniques
– once administered cannot be recalled
Drug Distribution
• At any given time, only a very small portion
of the total amount of a drug that is in the
body is actually in contact with its
receptors. Most of the administered drug is
found in areas of the body that are remote
from the drug’s site of action.
• Wide distribution often accounts for many
of the side effects of a drug
Membranes that Affect Drug
Distribution
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cell membranes
walls of the capillary vessels
blood-brain barrier
placental barrier
Blood Brain Barrier
• Required to protect brain from
– bacteria
– viruses
– toxins
• Required because neurons cannot regenerate
• Blocks the movement of most drugs into the brain
• Fat soluble drugs move best
Placental Barrier
• Drugs cross placental barrier primarily by passive
diffusion
• Fat soluble substances cross rapidly and without
limitation
• Placenta is not a barrier to drugs
• Psychoactive drugs will be present in the fetus at a
concentration quite similar to that in the mother
Termination of Drug Action
• Four main routes through which drugs leave body
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kidneys
lungs
bile
skin
• The major route is renal excretion
• Drug must be metabolized by enzymes in liver to
a form that can be excreted rapidly and reliably
Time Course
• Distribution Half Life: time for drug to
reach 50% of its peak concentration
• Elimination Half Life: time for drug
concentration to fall 50%
• Steady State Concentration: the level of
drug achieved in blood with repeated,
regular-interval dosing
Therapeutic Drug Monitoring
• Process of correlating the plasma level of
drugs with therapeutic response.
• Large scale clinical trials are performed and
blood samples are drawn at multiple time
periods (short term and long term)
• Statistical models used to monitor and
adjust patients dosage
Drug Tolerance
• A state of progressively decreasing responsiveness to a
drug. Person requires larger dose to achieve effect
• Three mechanisms:
– metabolic tolerance: liver produces extra enzymes and
metabolizes it faster
– cellular-adaptive tolerance: receptors adapt sensitivity or increase
or decrease number of receptors
– behavioral conditioning processes: environmental cues associated
with drug become conditioned stimuli that elicit conditioned
response opposite to the drug effect
Physical Dependence
• Needs drug to avoid withdrawal symptoms
– called abstinence syndrome
Pharmacodynamics: How Drugs
Act
Pharmacodynamics
• Study of the interactions of a drug and the
receptors responsible for the action of the
drug in the body.
• To produce an effect, a drug must bind to
and interact with specialized receptors,
usually located on cell membranes.
– Called -- drug-receptor binding
Six Points about Drug-Receptor
Interactions
• A receptor is usually a membrane-spanning
protein that has binding sites for an
endogenous neurotransmitter and
appropriate drug molecules
• This membrane-spanning protein is not a
simple globule but a continuous series of
either 7 or 12 alpha-helical coils embedded
in the membrane
Six Points
• The endogenous neurotransmitter (and presumably
drugs also) attaches inside the space between these
coils and is held in pace by ionic attractions
• This reversible ionic binding of the
neurotransmitter specific for that receptor may
activate the receptor, usually by changing the
structure of the protein. This change allows a
“signal,” or “information,” to be transmitted
through the receptor to the inside of the cell.
Six Points
• The intensity of the resulting transmembrane
signal is thought to be determined by the
percentage of receptors that are occupied by
molecules of neurotransmitter.
• A drug can affect the transmembrane signal by
binding either to the receptor for the endogenous
neurotransmitter or to a nearby site.
Binding of a Drug Results in One
of Three Possible Actions
• Binding to a receptor site normally
occupied by the endogenous
neurotransmitter can initiate a cellular
response similar or identical to that exerted
by the transmitter. The drug thus mimics
the action of the transmitter. This is termed
an agonistic action and the drug is termed
an agonist for that transmitter.
Three Actions
• Binding to a site near the binding site for
the endogenous transmitter can facilitate
transmitter binding. This is also an agonist
action.
Three Actions
• Binding to a receptor site normally occupied by a
neurotransmitter but not initiating a transmitterlike action blocks access of the transmitter to its
binding site, which inhibits the normal
physiological action of the transmitter. This is
called an antagonistic action and the drug is
termed and antagonist for that neurotransmitter or
receptor site.
Dose Response Curve
• Plot of the relation between drug doses and
the response elicited at each dose level.
Drug Safety and Effectiveness
• The dose of a drug that produces a specific
response varies considerably between individuals.
• ED50: The dose of a drug that produces the
desired effect in 50% of the subjects
• LD50: The dose that is lethal for 50% of the
subjects
• therapeutic index: The ratio of LD50 to ED50
Drug Interactions
• Main Effects -- Therapeutic Effects
• Side Effects
• With most drugs you have to have some side effects to get
the therapeutic effect.
• Serious side effects are possible
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serious allergies
blood disorders
liver or kidney toxicity
abnormalities in fetal development
Placebo Effects
• Placebo: a pharmacologically inert
substance that elicits a significant
therapeutic response.
• Produced by
– conditioning
– expectancy
– self liberation of endogenous neurotransmitters
Placebo Effects
• Placebos can therapeutically empower
patients to stimulate their
psychophysiological self-regulation abilities
• Patient biases and distortions have
consequences on therapeutic effectiveness
of a drug
• Must be aware of mental expectations,
social setting, predispositions