Transcript Drug Dosage and Clinical Responses

Drug Dosage and Clinical Responses
September 12, 2007
Frank F. Vincenzi
Learning Objectives
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Antagonism
Potency
Clinical efficacy
Slope of D-R curve
Quantal response
ED50, LD50, TI
Synergism
Summation
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Tolerance
Tachyphylaxis
Idiosyncrasy
Drug allergy
Therapeutic/side effects
Adverse effects
Toxicology
Factors Modifying Drug Responses
(The Big Three)
• Drug (pharmacodynamics)
• Dose (pharmaco/dynamics/kinetics)
• Route of Administration (pharmacokinetics)
Factors Modifying Drug Responses (cont):
The ‘big many’
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Tolerance
Dependence
Age
Weight
Sex
Pharmacogenetics
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Set
Setting
Dosing errors
Non-compliance
Drug interactions
Disease!
Attitude!
Antagonism
• Combined effect of the two drugs is less than the
sum of their individual effects
– Types of antagonism
Pharmacological (agonist/antagonist)
(pure antagonist + full agonist) (i.e., 0 + 6 = 1)
(partial agonist + full agonist) (i.e., 2 + 6 = 4)
– Chemical
– direct chemical interaction (e.g., chelation)
– Physiological
– Two drugs produce opposite effects on the same system
(epinephrine in the treatment of histamine-induced
bronchospasm)
Synergism
• The combined effect of two drugs is greater than
the sum of their individual effects
i.e., 1 + 1 = 6 or 0 + 4 = 10
(often called ‘potentiation’)
Potency and Clinical Efficacy/Efficiency
• Potency refers to the amount of drug necessary to
produce a certain effect. A drug which produces a
certain effect at 5 mg dosage is ten times more
potent than a drug which produces the same effect at
50 mg dosage.
• Clinical efficacy (or simply efficacy) refers to the
maximal clinical response that can be obtained by a
particular drug (morphine is more clinically
efficacious than aspirin as an analgesic) *
• Clinical efficiency is the bottom line of how well an
intervention actually works (includes compliance)
Healthy Volunteers (Medical Students?) and
Intravenous Sodium Amytal (n = 55)
Adapted from Clark’s Applied Pharmacology
Clinical Responses to Drugs are Often Expressed
Quantally: Quantal Dose-Response Curve
Medical Students (?) and Intravenous
Sodium Amytal (n = 55)
Adapted from Clark’s Applied Pharmacology
Population Quantal Dose-Response Curve
• Position is a reflection of drug potency. Drugs
that produce a certain effect at a low dose are
more potent than drugs that produce the same
effect at a higher dose.
• Slope is a reflection of the dispersion of
sensitivity to the drug among members of the
population. The steeper the slope the more
homogeneous the population.
Therapeutic Effect of Prazosin:
Lowering of Blood Pressure by 10 mm Hg
Isoniazid levels in patients subjected to a standard
dose - an example of pharmacokinetically
determined tolerance/sensitivity
Therapeutic and Side Effects of Drugs
• Therapeutic effect: the desired clinical
effect
• Side effects: any other clinical effects
(may include neutral or adverse events)
Frequency distribution and cumulative %
responses of a population to a drug
Calculation of Median Therapeutic Index
Different therapeutic indices of a given drug
with more than one therapeutic effect
Several measures of relative drug safety
• Median Therapeutic Index, TI = LD50/ED50
• ‘Conventional Index’ = LD1/ED1
• ‘Standard Safety Margin’ = ([LD1/ED99 - 1])*100
• ‘Standard Safety Margin’ = ([LD0.1/ED99.9 - 1])*100
Examples of relative toxicities of
some psychotropic drugs
Changes in therapeutic index of a chronically
administered barbiturate:
dispositional and cellular tolerance
Tolerance
• A condition produced by repeated or continued
exposure to a drug that produces decreased
responses to that drug when given at a certain
dosage - or that increased doses are needed to
maintain a certain level of response.
• (Cross tolerance refers to the same phenomenon
involving chemically or mechanistically related
drugs).
Subsets of Tolerance
• Tachyphylaxis
(e.g., indirectly acting sympathomimetic amines)
• Tolerance
– Dispositional
– Cellular
– Behavioral
Receptor Desensitization: One Potential
Mechanism of Cellular Tolerance
Reversible decrease in the sensitivity to agonist(s)
of responses mediated by a particular receptor or
receptor signaling pathway.
Example: agonist binds to the beta-receptor then betaadrenoceptor kinase (ARK), phosphorylates the betaadrenoceptor protein - this promotes the binding of
beta-arrestin and decreases interaction of the receptor
with the G protein, Gs.
Removal of agonist allows phosphatases to ‘reset’
the receptor.
Down Regulation of Receptors: Another
potential mechanism of cellular tolerance
Agonist-induced decrease in the number of available
receptors of a particular type. This decreases the
sensitivity of the system to responses mediated
by the receptor in question.
Example: altered receptor turnover that results in fewer
available receptors for activation in chronic opiate
usage, etc. (basis of tissue tolerance).
Up Regulation of Receptors
Antagonist- or ‘dis-use’-induced increase in the number
of available receptors of a particular type. This increases
the sensitivity of the system to responses mediated by the
receptor in question (increased number of spare
receptors).
Example: ‘denervation supersensitivity’
The ‘Therapeutic Window’
Ratio of the maximum concentration that is non-toxic in
most of the population (various toxicities) to the minimum
concentration that is effective in most of the population
(e.g., theophylline 10 - 20 µg/ml)
(avg.TD/ED in the ninth edition of Goodman & Gilman’s = 2.79 ± 3.2 (0.23 - 15)
THEREFORE:
A decimal point is a potentially lethal weapon!!
You MUST know pg, ng, µg, mg, g, kg, etc.
Practical limitations on clinical dosing:
Therapeutic and side effects of digitoxin
Adverse Drug Reactions
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Overdosage (includes interactions, genetics, suicide)
Side effects (most are predictable)
Secondary effects (e.g., overgrowth)
Idiosyncrasy (unpredictable, by definition)
Drug allergy (also called hypersensitivity)
Drugs Commonly Associated with Adverse
Reactions
• In hospitalized
patients:
• Leading to
hospitalization:
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digoxin
heparin
hydrochlorothiazide
spironolactone
aspirin
digoxin
hydrochlorothiazide
prednisone
warfarin
Adverse Drug Reactions Associated with
Multiple Drugs
Mortality Associated with
Multiple Drugs
Dependence
• “A cluster of cognitive, behavioral, and
physiological symptoms indicating that the
individual continues use of the substance despite
significant substance-related problems.”
(DSM-IV)
• Psychological - withdrawal mainly psychological
• Physical - the hallmark of physical
dependence is ‘physical’ withdrawal. May have
cross dependence.
Substance Abuse
• “…a maladaptive pattern of substance use
manifested by recurrent and significant adverse
consequences related to the repeated use of
substances.”
(DSM IV)
(Note: The criteria do not include tolerance, withdrawal or
a pattern of compulsive use. Also note, DSM IV never
uses the term ‘addiction’)
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Curiously: The category of substance abuse does not apply
to caffeine and nicotine - at least according to DSM IV.
ADDICTION: A more ‘official’ view
“Uncontrollable, compulsive drug seeking and
use, even in the face of negative health and
social consequences”
– Alan L. Leshner, Ph.D., Director of NIDA in:
The Brain: Understanding Neurobiology
Through the Study of Addiction