The Actions and Effects

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The Actions and Effects of Drugs and Poisons
Pharmacodynamics
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Terms
Action refers to the chemical mechanism of action

• Examples -
• aspirin is a general COX-inhibitor(irreversible)
• morphine binds to an opiate receptor
• penicillins inhibit a bacterial peptidase
• bicarbonate reacts with gastric HCl

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Terms

• Effects refer to observable symptomology
• aspirin - reduction of fever, pain relief
• morphine - pain relief, sedation, habituation
• penicillins - bacteria die, infection subsides
• bicarbonate - belch!

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Sites of Action
extracellular fluids- blood, lymph, GI
tract membranes - in, on, through intracellular
extracellular fluids- laxatives,
anticoagulants membranes - antifungals,
surfactants intracellular - lots
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Receptor Theory
A receptor is a biochemical entity, a protein,
simple or complex, located on, in, or through a
membrane, or intracellularly. It may contain a
single or multiple binding sites.
The stimulation of a receptor can have profound
effects on the entire organism.
agonist
has affinity for one or more receptor types
binding results in a response
antagonist
has affinity for one or more receptor types
binding results in no response
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Receptor Theory
affinity and efficacy
affinity and no efficacy
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Receptor Theory
Features of receptors

• glycoproteins, lipoproteins can be
  multi-subunited
• molecular weights in the 45-200 kD range
• binding is usually reversible and stereoselective
• binding specificity not necessarily absolute
• receptors are saturatable
• agonist activation leads to signal transduction
• more than one type of xenobiotic may be needed
  for activation
• magnitude of signal depends upon degree of
  binding
• intracellular mechanisms may amplify the signal
• xenobiotics can enhance, diminish, or block
  signal generation or transmission
• can be upregulated and downregulated

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Receptor Theory
agonist/antagonist - receptor interactions
specificity
selectivity
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Measurements of Drug Effects
dose - the amount of a drug needed at a given
time at a specific site to produce a desired
biological response.
Emax is a measure of efficacy.
EC50 is a measure of potency.
drug A
drug A
drug C
response (effect)
response (effect)
Emax
drug B
Emax
EC50
EC50
concentration of A
dose
Drug A could be a complete agonist, while drug B
would be a partial agonist.
Drug A is more potent than drug C.
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Measurements of Drug Effects
excretion half-life of a drug usually follows 1st
order kinetics
drugplasma
Biotransformation
rate kdrug1
Excretion
Distribution
Absorption
time after administration (min, hrs, days)
lndrugt-ktlndrug0
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reminder
Volume of Distribution
D - total amount of drug administered
drugplasma
VD - volume of distribution
This gives you an idea of how easily the drug is
absorbed into tissues or is bound to PP.
Also - if you have a large VD and have to achieve
a certain drugplasma for efficacy, you can
determine the amount of drug to be administered.
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Measurements of Drug Effects
toxic level
peak plasma level
drugplasma
therapeutic range
onset of action
duration of action
minimum effective level
latency
time after administration (min, hrs, days)
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Measurements of Drug Effects
Actual curves vary quite a bit.
drugplasma
time
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EQUIVALENCE
Chemical or pharmacological equivalence - Two or
more drug products which contain the same
chemical compound in the same amount in two or
more dosage forms and meet official FDA standards
are said to be chemically equivalent. The
"inactive" ingredients may be different.
Bioequivalence - Two chemically equivalent drugs
which, when administered to the same patient in
the same dose regime, produce an equivalent
blood/tissue concentration are bioequivalent.
Therapeutic equivalence - If two or more drugs
have about the same efficacy and safety. Note
that they might not be bioequivalent.
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Measurements of Drug Effects
Dose-Response Curves
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Therapeutic Effect
Lethality
Percent of population responding
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• organism
• dose
• route of administration

Median Effective Dose - ED50
dose or log dose
Median Lethal Dose - LD50
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Measurements of Drug Effects
Percent of population responding
Certain Safety Factor(CSF)
dose or log dose
Standard Safety Margin(SSM)
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Measurements of Drug Effects
Some scenarios
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Measurements of Drug Effects
drugplasma
dose or log10 dose
Therapeutic window(range) - drug substitutions
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ACUTE toxicity CHRONIC toxicity
Toxicity
No Threshold
toxic effects
there is no dose or exposure level which is safe
for health
limits of detection number of molecular
events acceptable risk
0
0
dose
Threshold
dose or exposure level below which no adverse
health effects are seen
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Drug Interactions
greater effects
diminished effects

• physiological
• pharmacological
• biochemical
• chemical

• additive
• summation
• synergistic

Drug Resistance
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Ligand-Receptor Binding

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LIGAND-GATED CHANNELS
Figure 4. 7 A Nicotinic Receptor Sodium Channel
Figure 4. 6 A Single Subunit of the Nicotinic
Receptor
Figure 4.8 Sodium Channel Opening and Closing
in Conjunction with the Binding of 2
Acetylcholine Molecules
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Second Messenger Systems
7 transmembrane helices
G-protein receptor
7-TM receptors
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